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1. Developmental interplay between transcriptional alterations and a targetable cytokine signaling dependency in pediatric ETO2::GLIS2 leukemia

Author: Verónica Alonso-Pérez, Klaudia Galant, Fabien Boudia, Elie Robert, Zakia Aid, Laurent Renou, Vilma Barroca, Saryiami Devanand, Loélia Babin, Virginie Rouiller-Fabre, Delphine Moison, Didier Busso, Guillaume Piton, Christophe Metereau, Nassera Abermil, Paola Ballerini, Pierre Hirsch, Rima Haddad, Jelena Martinovic, Arnaud Petit, Hélène Lapillonne, Erika Brunet, Thomas Mercher, and Françoise Pflumio
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Several fusion oncogenes showing a higher incidence in pediatric acute myeloid leukemia (AML) are associated with heterogeneous megakaryoblastic and other myeloid features. Here we addressed how developmental mechanisms influence human leukemogenesis by ETO2::GLIS2, associated with dismal prognosis. Methods We created novel ETO2::GLIS2 models of leukemogenesis through lentiviral transduction and CRISPR-Cas9 gene editing of human fetal and post-natal hematopoietic stem/progenitor cells (HSPCs), performed in-depth characterization of ETO2::GLIS2 transformed cells through multiple omics and compared them to patient samples. This led to a preclinical assay using patient-derived-xenograft models to test a combination of two clinically-relevant molecules. Results We showed that ETO2::GLIS2 expression in primary human fetal CD34+ hematopoietic cells led to more efficient in vivo leukemia development than expression in post-natal cells. Moreover, cord blood-derived leukemogenesis has a major dependency on the presence of human cytokines, including IL3 and SCF. Single cell transcriptomes revealed that this cytokine environment controlled two ETO2::GLIS2-transformed states that were also observed in primary patient cells. Importantly, this cytokine sensitivity may be therapeutically-exploited as combined MEK and BCL2 inhibition showed higher efficiency than individual molecules to reduce leukemia progression in vivo. Conclusions Our study uncovers an interplay between the cytokine milieu and transcriptional programs that extends a developmental window of permissiveness to transformation by the ETO2::GLIS2 AML fusion oncogene, controls the intratumoral cellular heterogeneity, and offers a ground-breaking therapeutical opportunity by a targeted combination strategy.
Published: 2024
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2. The ETO2 transcriptional cofactor maintains acute leukemia by driving a MYB/EP300‐dependent stemness program

Author: Alexandre Fagnan, Zakia Aid, Marie Baille, Aneta Drakul, Elie Robert, Cécile K. Lopez, Cécile Thirant, Yann Lecluse, Julie Rivière, Cathy Ignacimouttou, Silvia Salmoiraghi, Eduardo Anguita, Audrey Naimo, Christophe Marzac, Françoise Pflumio, Sébastien Malinge, Christian Wichmann, Yun Huang, Camille Lobry, Julie Chaumeil, Eric Soler, Jean‐Pierre Bourquin, Claus Nerlov, Olivier A. Bernard, Juerg Schwaller, and Thomas Mercher
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Abstract: Abstract Transcriptional cofactors of the ETO family are recurrent fusion partners in acute leukemia. We characterized the ETO2 regulome by integrating transcriptomic and chromatin binding analyses in human erythroleukemia xenografts and controlled ETO2 depletion models. We demonstrate that beyond its well‐established repressive activity, ETO2 directly activates transcription of MYB, among other genes. The ETO2‐activated signature is associated with a poorer prognosis in erythroleukemia but also in other acute myeloid and lymphoid leukemia subtypes. Mechanistically, ETO2 colocalizes with EP300 and MYB at enhancers supporting the existence of an ETO2/MYB feedforward transcription activation loop (e.g., on MYB itself). Both small‐molecule and PROTAC‐mediated inhibition of EP300 acetyltransferases strongly reduced ETO2 protein, chromatin binding, and ETO2‐activated transcripts. Taken together, our data show that ETO2 positively enforces a leukemia maintenance program that is mediated in part by the MYB transcription factor and that relies on acetyltransferase cofactors to stabilize ETO2 scaffolding activity.
Published: 2024
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3. CASZ1 upregulates PI3K-AKT-mTOR signaling and promotes T-cell acute lymphoblastic leukemia

Author: Bruno A. Cardoso, Mafalda Duque, Ana Gírio, Rita Fragoso, Mariana L. Oliveira, James R. Allen, Leila R. Martins, Nádia C. Correia, André Bortolini Silveira, Alexandra Veloso, Shunsuke Kimura, Lisa Demoen, Filip Matthijssens, Sima Jeha, Cheng Cheng, Ching-Hon Pui, Ana R. Grosso, João L. Neto, Sérgio F. de Almeida, Pieter Van Vlieberghe, Charles G. Mullighan, J. Andres Yunes, David M. Langenau, Françoise Pflumio, and João T. Barata
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Abstract: CASZ1 is a conserved transcription factor involved in neural development, blood vessel assembly and heart morphogenesis. CASZ1 has been implicated in cancer, either suppressing or promoting tumor development depending on the tissue. However, the impact of CASZ1 on hematological tumors remains unknown. Here, we show that the T-cell oncogenic transcription factor TAL1 is a direct positive regulator of CASZ1, that T-cell acute lymphoblastic leukemia (T-ALL) samples at diagnosis overexpress CASZ1b isoform, and that CASZ1b expression in patient samples correlates with PI3K-AKT-mTOR signaling pathway activation. In agreement, overexpression of CASZ1b in both Ba/F3 and T-ALL cells leads to the activation of PI3K signaling pathway, which is required for CASZ1b-mediated transformation of Ba/F3 cells in vitro and malignant expansion in vivo. We further demonstrate that CASZ1b cooperates with activated NOTCH1 to promote T-ALL development in zebrafish, and that CASZ1b protects human T-ALL cells from serum deprivation and treatment with chemotherapeutic drugs. Taken together, our studies indicate that CASZ1b is a TAL1-regulated gene that promotes T-ALL development and resistance to chemotherapy.
Published: 2023
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4. CDKN1A is a target for phagocytosis-mediated cellular immunotherapy in acute leukemia

Author: Awatef Allouch, Laurent Voisin, Yanyan Zhang, Syed Qasim Raza, Yann Lecluse, Julien Calvo, Dorothée Selimoglu-Buet, Stéphane de Botton, Fawzia Louache, Françoise Pflumio, Eric Solary, and Jean-Luc Perfettini
Subjects: Science
Abstract: Inducing phagocytic capacities of tumour-associated macrophages to eliminate cancer cells is a promising immunotherapy. Here, the authors show that engineered macrophages overexpressing CDKN1A/p21 reduce leukaemic tumour burden and increase survival in preclinical mouse models of human T-ALL.
Published: 2022
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5. Downregulation of Glutamine Synthetase, not glutaminolysis, is responsible for glutamine addiction in Notch1‐driven acute lymphoblastic leukemia

Author: Tra Ly Nguyen, Marie‐Julie Nokin, Silvia Terés, Mercedes Tomé, Clément Bodineau, Oriane Galmar, Jean‐Max Pasquet, Benoit Rousseau, Sebastian vanLiempd, Juan Manuel Falcon‐Perez, Elodie Richard, Elodie Muzotte, Hamid‐Reza Rezvani, Muriel Priault, Marion Bouchecareilh, Isabelle Redonnet‐Vernhet, Julien Calvo, Benjamin Uzan, Françoise Pflumio, Patricia Fuentes, Maria L. Toribio, Abdel‐Majid Khatib, Pierre Soubeyran, Piedad del Socorro Murdoch, and Raúl V. Durán
Subjects: glutamine, glutamine synthetase, metabolic addiction, mTORC1, Notch1, T‐cell acute lymphoblastic leukemia, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: The cellular receptor Notch1 is a central regulator of T‐cell development, and as a consequence, Notch1 pathway appears upregulated in > 65% of the cases of T‐cell acute lymphoblastic leukemia (T‐ALL). However, strategies targeting Notch1 signaling render only modest results in the clinic due to treatment resistance and severe side effects. While many investigations reported the different aspects of tumor cell growth and leukemia progression controlled by Notch1, less is known regarding the modifications of cellular metabolism induced by Notch1 upregulation in T‐ALL. Previously, glutaminolysis inhibition has been proposed to synergize with anti‐Notch therapies in T‐ALL models. In this work, we report that Notch1 upregulation in T‐ALL induced a change in the metabolism of the important amino acid glutamine, preventing glutamine synthesis through the downregulation of glutamine synthetase (GS). Downregulation of GS was responsible for glutamine addiction in Notch1‐driven T‐ALL both in vitro and in vivo. Our results also confirmed an increase in glutaminolysis mediated by Notch1. Increased glutaminolysis resulted in the activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway, a central controller of cell growth. However, glutaminolysis did not play any role in Notch1‐induced glutamine addiction. Finally, the combined treatment targeting mTORC1 and limiting glutamine availability had a synergistic effect to induce apoptosis and to prevent Notch1‐driven leukemia progression. Our results placed glutamine limitation and mTORC1 inhibition as a potential therapy against Notch1‐driven leukemia.
Published: 2021
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6. Human hematopoietic stem/progenitor cells display reactive oxygen species-dependent long-term hematopoietic defects after exposure to low doses of ionizing radiations

Author: Elia Henry, Inès Souissi-Sahraoui, Margaux Deynoux, Andréas Lefèvre, Vilma Barroca, Anna Campalans, Véronique Ménard, Julien Calvo, Françoise Pflumio, and Marie-Laure Arcangeli
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Abstract: Hematopoietic stem cells are responsible for life-long blood cell production and are highly sensitive to exogenous stresses. The effects of low doses of ionizing radiations on radiosensitive tissues such as the hematopoietic tissue are still unknown despite their increasing use in medical imaging. Here, we study the consequences of low doses of ionizing radiations on differentiation and self-renewal capacities of human primary hematopoietic stem/progenitor cells (HSPC). We found that a single 20 mGy dose impairs the hematopoietic reconstitution potential of human HSPC but not their differentiation properties. In contrast to high irradiation doses, low doses of irradiation do not induce DNA double strand breaks in HSPC but, similar to high doses, induce a rapid and transient increase of reactive oxygen species (ROS) that promotes activation of the p38MAPK pathway. HSPC treatment with ROS scavengers or p38MAPK inhibitor prior exposure to 20 mGy irradiation abolishes the 20 mGy-induced defects indicating that ROS and p38MAPK pathways are transducers of low doses of radiation effects. Taken together, these results show that a 20 mGy dose of ionizing radiation reduces the reconstitution potential of HSPC suggesting an effect on the self-renewal potential of human hematopoietic stem cells and pinpointing ROS or the p38MAPK as therapeutic targets. Inhibition of ROS or the p38MAPK pathway protects human primary HSPC from low-dose irradiation toxicity.
Published: 2020
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7. β-Catenin and its new partner FOXO3 shake T-ALL

Author: Julien Calvo and Françoise Pflumio
Subjects: Immunology, Cell Biology, Hematology, Biochemistry
Published: 2023
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8. Homeobox protein TLX3 activates miR-125b expression to promote T-cell acute lymphoblastic leukemia

Author: Laurent Renou, Pierre-Yves Boelle, Caroline Deswarte, Salvatore Spicuglia, Aissa Benyoucef, Julien Calvo, Benjamin Uzan, Mohamed Belhocine, Agata Cieslak, Judith Landman-Parker, Andre Baruchel, Vahid Asnafi, Françoise Pflumio, Paola Ballerini, and Irina Naguibneva
Subjects: Specialties of internal medicine, RC581-951
Abstract: Abstract: The oncogenic mechanisms driven by aberrantly expressed transcription factors in T-cell acute leukemia (T-ALL) are still elusive. MicroRNAs (miRNAs) play an important role in normal development and pathologies. Here, we examined the expression of 738 miRNA species in 41 newly diagnosed pediatric T-ALLs and in human thymus-derived cells. We found that expression of 2 clustered miRNAs, miR-125b/99a, peaks in primitive T cells and is upregulated in the T leukemia homeobox 3 (TLX3)–positive subtype of T-ALL. Using loss- and gain-of-function approaches, we established functional relationships between TLX3 and miR-125b. Both TLX3 and miR-125b support in vitro cell growth and in vivo invasiveness of T-ALL. Besides, ectopic expression of TLX3 or miR-125b in human hematopoietic progenitor cells enhances production of T-cell progenitors and favors their accumulation at immature stages of T-cell development resembling the differentiation arrest observed in TLX3 T-ALL. Ectopic miR-125b also remarkably accelerated leukemia in a xenograft model, suggesting that miR125b is an important mediator of the TLX3-mediated transformation program that takes place in immature T-cell progenitors. Mechanistically, TLX3-mediated activation of miR-125b may impact T-cell differentiation in part via repression of Ets1 and CBFβ genes, 2 regulators of T-lineage. Finally, we established that TLX3 directly regulates miR-125b production through binding and transactivation of LINC00478, a long noncoding RNA gene, which is the host of miR-99a/Let-7c/miR-125b. Altogether, our results reveal an original functional link between TLX3 and oncogenic miR-125b in T-ALL development.
Published: 2017
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9. Hypoxia Regulates Lymphoid Development of Human Hematopoietic Progenitors

Author: Sara Chabi, Benjamin Uzan, Irina Naguibneva, Julien Rucci, Lucine Fahy, Julien Calvo, Marie-Laure Arcangeli, Frédéric Mazurier, Françoise Pflumio, and Rima Haddad
Subjects: Biology (General), QH301-705.5
Abstract: Summary: Hypoxia plays a major role in the physiology of hematopoietic and immune niches. Important clues from works in mouse have paved the way to investigate the role of low O2 levels in hematopoiesis. However, whether hypoxia impacts the initial steps of human lymphopoiesis remains unexplored. Here, we show that hypoxia regulates cellular and metabolic profiles of umbilical cord blood (UCB)-derived hematopoietic progenitor cells. Hypoxia more specifically enhances in vitro lymphoid differentiation potentials of lymphoid-primed multipotent progenitors (LMPPs) and pro-T/natural killer (NK) cells and in vivo B cell potential of LMPPs. In accordance, hypoxia exacerbates the lymphoid gene expression profile through hypoxia-inducible factor (HIF)-1α (for LMPPs) and HIF-2α (for pro-T/NK). Moreover, loss of HIF-1/2α expression seriously impedes NK and B cell production from LMPPs and pro-T/NK. Our study describes how hypoxia contributes to the lymphoid development of human progenitors and reveals the implication of the HIF pathway in LMPPs and pro-T/NK-cell lymphoid identities. : Chabi et al. show that low oxygen levels promote the development of human lymphoid cells from umbilical cord blood progenitors. The work also highlights how hypoxia-inducible factors, the major actors of hypoxia cell response, are involved in the early steps of human lymphopoiesis by supporting cell differentiation and production.
Published: 2019
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10. Supplementary Figures 1 - 3, Table 1 from Triggering the TCR Developmental Checkpoint Activates a Therapeutically Targetable Tumor Suppressive Pathway in T-cell Leukemia

Author: Vahid Asnafi, Jacques Ghysdael, Elizabeth Macintyre, Olivier Hermine, David-Alexandre Gross, Lucienne Chatenoud, Salvatore Spicuglia, Hervé Dombret, Norbert Ifrah, Françoise Pflumio, Els Verhoeyen, François-Loïc Cosset, Michael Dussiot, Melania Tesio, Ludovic Lhermitte, Cindy Da Costa de Jesus, Mohamed Belhocine, Benedetta Zaniboni, Francesca Rocchetti, Christine Tran Quang, Nuno R. dos Santos, and Amélie Trinquand
Abstract: Supplementary Figure 1. Anti-CD3 stimulation of primary human T-ALLs. Supplementary Figure 2. TCR stimulation by in vivo administration of agonistic monoclonal antibody in a preventive setting inhibits human TCR+ T-ALL development. Supplementary Figure 3. TCR signaling is essential to the anti-leukemic effect of OKT3. Supplementary Table 1. Immunophenotypic and oncogenic characteristics of T-ALL samples.
Published: 2023
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11. Supplementary Methods, Figure Legends, Table Legend from Triggering the TCR Developmental Checkpoint Activates a Therapeutically Targetable Tumor Suppressive Pathway in T-cell Leukemia

Author: Vahid Asnafi, Jacques Ghysdael, Elizabeth Macintyre, Olivier Hermine, David-Alexandre Gross, Lucienne Chatenoud, Salvatore Spicuglia, Hervé Dombret, Norbert Ifrah, Françoise Pflumio, Els Verhoeyen, François-Loïc Cosset, Michael Dussiot, Melania Tesio, Ludovic Lhermitte, Cindy Da Costa de Jesus, Mohamed Belhocine, Benedetta Zaniboni, Francesca Rocchetti, Christine Tran Quang, Nuno R. dos Santos, and Amélie Trinquand
Abstract: Supplementary Methods, Figure Legends, Table Legend
Published: 2023
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12. Supplementary Figures and Legends from Ontogenic Changes in Hematopoietic Hierarchy Determine Pediatric Specificity and Disease Phenotype in Fusion Oncogene–Driven Myeloid Leukemia

Author: Thomas Mercher, Juerg Schwaller, Françoise Pflumio, Arnaud Petit, Berthold Göttgens, Olivier A. Bernard, Isabelle Godin, Camille Lobry, Nathalie Droin, Claus Nerlov, Sébastien Malinge, Franco Locatelli, Riccardo Masetti, Muriel Gaudry, William Vainchenker, Antoine H.F.M. Peters, Eric Delabesse, Jean Luc Villeval, Loélia Babin, Erika Brunet, Yann Lecluse, Bastien Job, M'Boyba Diop, Sarah J. Kinston, Marie-Laure Arcangeli, Alexandre Fagnan, Cécile Thirant, Fabien Boudia, Hélène Lapillonne, Chrystèle Bilhou-Nabera, Paola Ballerini, Zakia Aid, Elie Robert, Vaia Stavropoulou, Esteve Noguera, and Cécile K. Lopez
Abstract: Supplementary Figures and Legends
Published: 2023
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13. Data from Ontogenic Changes in Hematopoietic Hierarchy Determine Pediatric Specificity and Disease Phenotype in Fusion Oncogene–Driven Myeloid Leukemia

Author: Thomas Mercher, Juerg Schwaller, Françoise Pflumio, Arnaud Petit, Berthold Göttgens, Olivier A. Bernard, Isabelle Godin, Camille Lobry, Nathalie Droin, Claus Nerlov, Sébastien Malinge, Franco Locatelli, Riccardo Masetti, Muriel Gaudry, William Vainchenker, Antoine H.F.M. Peters, Eric Delabesse, Jean Luc Villeval, Loélia Babin, Erika Brunet, Yann Lecluse, Bastien Job, M'Boyba Diop, Sarah J. Kinston, Marie-Laure Arcangeli, Alexandre Fagnan, Cécile Thirant, Fabien Boudia, Hélène Lapillonne, Chrystèle Bilhou-Nabera, Paola Ballerini, Zakia Aid, Elie Robert, Vaia Stavropoulou, Esteve Noguera, and Cécile K. Lopez
Abstract: Fusion oncogenes are prevalent in several pediatric cancers, yet little is known about the specific associations between age and phenotype. We observed that fusion oncogenes, such as ETO2–GLIS2, are associated with acute megakaryoblastic or other myeloid leukemia subtypes in an age-dependent manner. Analysis of a novel inducible transgenic mouse model showed that ETO2–GLIS2 expression in fetal hematopoietic stem cells induced rapid megakaryoblastic leukemia whereas expression in adult bone marrow hematopoietic stem cells resulted in a shift toward myeloid transformation with a strikingly delayed in vivo leukemogenic potential. Chromatin accessibility and single-cell transcriptome analyses indicate ontogeny-dependent intrinsic and ETO2–GLIS2-induced differences in the activities of key transcription factors, including ERG, SPI1, GATA1, and CEBPA. Importantly, switching off the fusion oncogene restored terminal differentiation of the leukemic blasts. Together, these data show that aggressiveness and phenotypes in pediatric acute myeloid leukemia result from an ontogeny-related differential susceptibility to transformation by fusion oncogenes.Significance:This work demonstrates that the clinical phenotype of pediatric acute myeloid leukemia is determined by ontogeny-dependent susceptibility for transformation by oncogenic fusion genes. The phenotype is maintained by potentially reversible alteration of key transcription factors, indicating that targeting of the fusions may overcome the differentiation blockage and revert the leukemic state.See related commentary by Cruz Hernandez and Vyas, p. 1653.This article is highlighted in the In This Issue feature, p. 1631
Published: 2023
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14. Supplementary Tables 1 to 11 from Ontogenic Changes in Hematopoietic Hierarchy Determine Pediatric Specificity and Disease Phenotype in Fusion Oncogene–Driven Myeloid Leukemia

Author: Thomas Mercher, Juerg Schwaller, Françoise Pflumio, Arnaud Petit, Berthold Göttgens, Olivier A. Bernard, Isabelle Godin, Camille Lobry, Nathalie Droin, Claus Nerlov, Sébastien Malinge, Franco Locatelli, Riccardo Masetti, Muriel Gaudry, William Vainchenker, Antoine H.F.M. Peters, Eric Delabesse, Jean Luc Villeval, Loélia Babin, Erika Brunet, Yann Lecluse, Bastien Job, M'Boyba Diop, Sarah J. Kinston, Marie-Laure Arcangeli, Alexandre Fagnan, Cécile Thirant, Fabien Boudia, Hélène Lapillonne, Chrystèle Bilhou-Nabera, Paola Ballerini, Zakia Aid, Elie Robert, Vaia Stavropoulou, Esteve Noguera, and Cécile K. Lopez
Abstract: Supplementary Tables 1 to 11
Published: 2023
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15. Concurrent CDX2 cis-deregulation and UBTF::ATXN7L3 fusion define a novel high-risk subtype of B-cell ALL

Author: Marie Passet, Rathana Kim, Stéphanie Gachet, François Sigaux, Julie Chaumeil, Ava Galland, Thomas Sexton, Samuel Quentin, Lucie Hernandez, Lise Larcher, Hugo Bergugnat, Tao Ye, Nezih Karasu, Aurélie Caye, Beate Heizmann, Isabelle Duluc, Patrice Chevallier, Philippe Rousselot, Françoise Huguet, Thibaut Leguay, Mathilde Hunault, Françoise Pflumio, Jean-Noël Freund, Camille Lobry, Véronique Lhéritier, Hervé Dombret, Claire Domon-Dell, Jean Soulier, Nicolas Boissel, and Emmanuelle Clappier
Subjects: Immunology, Cell Biology, Hematology, Biochemistry
Abstract: Oncogenic alterations underlying B-cell acute lymphoblastic leukemia (B-ALL) in adults remain incompletely elucidated. To uncover novel oncogenic drivers, we performed RNA sequencing and whole-genome analyses in a large cohort of unresolved B-ALL. We identified a novel subtype characterized by a distinct gene expression signature and the unique association of 2 genomic microdeletions. The 17q21.31 microdeletion resulted in a UBTF::ATXN7L3 fusion transcript encoding a chimeric protein. The 13q12.2 deletion resulted in monoallelic ectopic expression of the homeobox transcription factor CDX2, located 138 kb in cis from the deletion. Using 4C-sequencing and CRISPR interference experiments, we elucidated the mechanism of CDX2 cis-deregulation, involving PAN3 enhancer hijacking. CDX2/UBTF ALL (n = 26) harbored a distinct pattern of additional alterations including 1q gain and CXCR4 activating mutations. Within adult patients with Ph− B-ALL enrolled in GRAALL trials, patients with CDX2/UBTF ALL (n = 17/723, 2.4%) were young (median age, 31 years) and dramatically enriched in females (male/female ratio, 0.2, P = .002). They commonly presented with a pro-B phenotype ALL and moderate blast cell infiltration. They had poor response to treatment including a higher risk of failure to first induction course (19% vs 3%, P = .017) and higher post-induction minimal residual disease (MRD) levels (MRD ≥ 10−4, 93% vs 46%, P < .001). This early resistance to treatment translated into a significantly higher cumulative incidence of relapse (75.0% vs 32.4%, P = .004) in univariate and multivariate analyses. In conclusion, we discovered a novel B-ALL entity defined by the unique combination of CDX2 cis-deregulation and UBTF::ATXN7L3 fusion, representing a high-risk disease in young adults.
Published: 2022
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16. REDD1 is a gatekeeper of murine hematopoietic stem cell functions during stress responses

Author: Vilma Barroca, Elia Henry, Nathalie Dechamps, Laurent Renou, Paul Chaintreuil, Rohan Kulkarni, Saiyirami Devanand, Arnaud Jacquel, Guillaume Robert, Patrick Auberger, Françoise Pflumio, and Marie-Laure Arcangeli
Subjects: Cancer Research, Oncology, Hematology
Published: 2022
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17. Transcriptional profiling of β-2M−SPα-6+THY1+ spermatogonial stem cells in human spermatogenesis

Author: Maelle Givelet, Virginie Firlej, Bruno Lassalle, Anne Sophie Gille, Clementine Lapoujade, Isabelle Holtzman, Amandine Jarysta, Farahd Haghighirad, Florent Dumont, Sébastien Jacques, Franck Letourneur, Françoise Pflumio, Isabelle Allemand, Catherine Patrat, Nicolas Thiounn, Jean Philippe Wolf, Lydia Riou, Virginie Barraud-Lange, and Pierre Fouchet
Subjects: Genetics, Cell Biology, Biochemistry, Developmental Biology
Published: 2022
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18. Data from Epigenetic Silencing Affects l-Asparaginase Sensitivity and Predicts Outcome in T-ALL

Author: Vahid Asnafi, Nicolas Boissel, Mathilde Hunault, Elizabeth Macintyre, Hervé Dombret, Norbert Ifrah, Stéphane Leprêtre, Françoise Huguet, Yves Chalandon, Carlos Graux, Thibaut Leguay, Françoise Pflumio, Denis Puthier, Salvatore Spicuglia, Xavier Thomas, Charlotte Smith, Mohamed Belhocine, Mehdi Latiri, Etienne Lengliné, and Aurore Touzart
Abstract: Purpose:Biological explanation for discrepancies in patient-related response to chemotherapy depending on the underlying oncogenic events is a promising research area. TLX1- or TLX3-deregulated T-cell acute lymphoblastic leukemias (T-ALL; TLX1/3+) share an immature cortical phenotype and similar transcriptional signatures. However, their prognostic impacts differ, and inconsistent clinical outcome has been reported for TLX3. We therefore hypothesized that the overlapping transcriptional profiles of TLX1+ and TLX3+ T-ALLs would allow identification of candidate genes, which might determine their distinct clinical outcomes.Experimental Design:We compared TLX1+ and TLX3+ adult T-ALL outcome in the successive French national LALA-94 and GRAALL-2003/2005 multicentric trials and analyzed transcriptomic data to identify differentially expressed genes. Epigenetic regulation of asparagine synthetase (ASNS) and in vitro l-asparaginase sensitivity were evaluated for T-ALL cell lines and primary samples.Results:We show that TLX1+ patients expressed low levels of ASNS when compared with TLX3+ and TLX-negative patients, due to epigenetic silencing of ASNS by both DNA methylation and a decrease of active histone marks. Promoter methylation of the ASNS gene correlated with l-asparaginase sensitivity in both T-ALL cell lines and patient-derived xenografts. Finally, ASNS promoter methylation was an independent prognostic factor for both event-free survival [HR, 0.42; 95% confidence interval (CI), 0.24–0.71; P = 0.001] and overall survival (HR, 0.40; 95% CI, 0.23–0.70; P = 0.02) in 160 GRAALL-2003/2005 T-ALL patients and also in an independent series of 47 LL03-treated T lymphoblastic lymphomas (P = 0.012).Conclusions:We conclude that ASNS methylation status at diagnosis may allow individual adaptation of l-asparaginase dose.
Published: 2023
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19. High caspase 3 and vulnerability to dual BCL2 family inhibition define ETO2::GLIS2 pediatric leukemia

Author: Zakia Aid, Elie Robert, Cécile K. Lopez, Maxence Bourgoin, Fabien Boudia, Melchior Le Mene, Julie Riviere, Marie Baille, Salima Benbarche, Laurent Renou, Alexandre Fagnan, Cécile Thirant, Laetitia Federici, Laure Touchard, Yann Lecluse, Anton Jetten, Birgit Geoerger, Hélène Lapillonne, Eric Solary, Muriel Gaudry, Soheil Meshinchi, Françoise Pflumio, Patrick Auberger, Camille Lobry, Arnaud Petit, Arnaud Jacquel, and Thomas Mercher
Subjects: Cancer Research, Oncology, Hematology
Abstract: Pediatric acute myeloid leukemia expressing the ETO2::GLIS2 fusion oncogene is associated with dismal prognosis. Previous studies have shown that ETO2::GLIS2 can efficiently induce leukemia development associated with strong transcriptional changes but those amenable to pharmacological targeting remained to be identified. By studying an inducible ETO2::GLIS2 cellular model, we uncovered that de novo ETO2::GLIS2 expression in human cells led to increased CASP3 transcription, CASP3 activation, and cell death. Patient-derived ETO2::GLIS2
Published: 2022

20. Human hematopoietic stem/progenitor cells display reactive oxygen species-dependent long-term hematopoietic defects after exposure to low doses of ionizing radiations

Author: Vilma Barroca, Andreas Lefevre, Véronique Ménard, Marie-Laure Arcangeli, Elia Henry, Inès Souissi-Sahraoui, Françoise Pflumio, Anna Campalans, Julien Calvo, and Margaux Deynoux
Subjects: chemistry.chemical_classification, Reactive oxygen species, Cellular differentiation, medicine.medical_treatment, Hematopoietic Tissue, Hematology, Hematopoietic stem cell transplantation, Cell biology, Blood cell, Haematopoiesis, medicine.anatomical_structure, chemistry, medicine, Stem cell, Progenitor cell
Abstract: Hematopoietic stem cells are responsible for life-long blood cell production and are highly sensitive to exogenous stresses. The effects of low doses of ionizing radiations on radiosensitive tissues such as the hematopoietic tissue are still unknown despite their increasing use in medical imaging. Here, we study the consequences of low doses of ionizing radiations on differentiation and self-renewal capacities of human primary hematopoietic stem/progenitor cells (HSPC). We found that a single 20 mGy dose impairs the hematopoietic reconstitution potential of human HSPC but not their differentiation properties. In contrast to high irradiation doses, low doses of irradiation do not induce DNA double strand breaks in HSPC but, similar to high doses, induce a rapid and transient increase of reactive oxygen species (ROS) that promotes activation of the p38MAPK pathway. HSPC treatment with ROS scavengers or p38MAPK inhibitor prior exposure to 20 mGy irradiation abolishes the 20 mGy-induced defects indicating that ROS and p38MAPK pathways are transducers of low doses of radiation effects. Taken together, these results show that a 20 mGy dose of ionizing radiation reduces the reconstitution potential of HSPC suggesting an effect on the self-renewal potential of human hematopoietic stem cells and pinpointing ROS or the p38MAPK as therapeutic targets. Inhibition of ROS or the p38MAPK pathway protects human primary HSPC from low-dose irradiation toxicity.
Published: 2019
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21. Frontline Science: Exhaustion and senescence marker profiles on human T cells in BRGSF-A2 humanized mice resemble those in human samples

Author: Marie-Laure Arcangeli, James P. Di Santo, Françoise Pflumio, Soledad Henriquez, Roger Le Grand, Olivier Lambotte, Christine Bourgeois, Laura Labarthe, and Nicolas Legrand
Subjects: Adult, Male, 0301 basic medicine, Senescence, T-Lymphocytes, Immunology, CD34, Spleen, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, TIGIT, Mice, Inbred NOD, PD-L1, HLA-A2 Antigen, Leukocytes, medicine, Animals, Humans, Immunology and Allergy, Receptors, Immunologic, Cellular Senescence, Aged, Mice, Knockout, Mice, Inbred BALB C, biology, Cell Biology, Middle Aged, Molecular biology, Healthy Volunteers, DNA-Binding Proteins, 030104 developmental biology, medicine.anatomical_structure, fms-Like Tyrosine Kinase 3, Cord blood, biology.protein, Female, Bone marrow, Biomarkers, Interleukin Receptor Common gamma Subunit, 030215 immunology
Abstract: This work sought to confirm the human-like expression of exhaustion and senescence markers in a mouse model with a humanized immune system (HIS): the Balb/c Rag2KO IL2rgcKO SirpαNOD Flk2KO HLA-A2HHD (BRGSF-A2) mouse reconstituted with human CD34+ cord blood cells. With regard to senescence markers, the percentage of CD57+ T cells was higher in the bone marrow (BM) than in the spleen or blood. The same was true for KLRG1+ hCD8+ T cells. With regard to exhaustion markers, the percentage of programmed death 1 (PD-1+) T cells was higher in the BM than in the spleen or blood; the same was true for TIGIT+ hCD4+ cells. These tissue-specific differences were related to both higher proportions of memory T cells in BM and intrinsic differences in expression within the memory fraction. In blood samples from HIS mice and healthy human donors (HDs), we found that the percentage of KLRG1+ cells among hCD8+ T cells was lower in HIS compared to HDs. The opposite was true for CD4+ T cells. Unexpectedly, a high frequency of KLRG1+ cells was observed among naive T cells in HIS mice. CD57 expression on T cells was similar in blood samples from HIS mice and HDs. Likewise, PD-1 expression was similar in the two systems, although a relatively low proportion of HIS hCD4+ T cells expressed TIGIT. The BRGSF-A2 HIS mouse's exhaustion and senescence profile was tissue specific and relatively human like; hence, this mouse might be a valuable tool for determining the preclinical efficacy of immunotherapies.
Published: 2019
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22. A Recurrent Activating Missense Mutation in Waldenström Macroglobulinemia Affects the DNA Binding of the ETS Transcription Factor SPI1 and Enhances Proliferation

Author: Nathalie Droin, Philippe Rameau, Philippe Dessen, Florence Nguyen-Khac, Bilyana Stoilova, Elena Mylonas, Marine Armand, Damien Roos-Weil, Olivier Bernard, Els Verhoeyen, Paresh Vyas, Said Aoufouchi, Marlen Metzner, Françoise Pflumio, Frédéric Charlotte, Vincent Ribrag, Diane Lara, Olivier Elemento, Pierre Morel, Eric Durot, Cécile Hérate, Pascale Cornillet-Lefebvre, Véronique Della-Valle, Hussein Ghamlouch, Virginie Ropars, Frederik Damm, Nabih Azar, Christel Guillouf, François-Loïc Cosset, Camille Decaudin, Valérie Camara-Clayette, M'Boyba Diop, Veronique Leblond, Thomas Mercher, Jean-Baptiste Charbonnier, Rima Haddad, Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Enveloppe Nucléaire, Télomères et Réparation de l’ADN (INTGEN), Département Biochimie, Biophysique et Biologie Structurale (B3S), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Department of Haematology, Haemostasis, Oncology and Stem Cell Transplantation (MHH), Hannover Medical School [Hannover] (MHH), CEA Direction des Sciences du Vivant (CEA/DSV), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), The Weatherall Institute of Molecular Medicine, University of Oxford [Oxford], Weill Medical College of Cornell University [New York], Institut Gustave Roussy (IGR), Plateforme de Bioinformatique [Gustave Roussy], Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de recherche translationnelle (Labo RT), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Hématologie clinique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU), Département d'hématologie [Gustave Roussy], Laboratoire d'hématologie, Centre Hospitalier Universitaire de Reims (CHU Reims), Plateforme imagerie et cytométrie (PFIC), Ligue Nationale Contre le Cancer - Paris, Ligue Nationale Contre le Cancer (LNCC), Brigham and Women's Hospital [Boston], Stabilité Génétique et Oncogenèse (UMR 8200), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie Biologique [CHU Pitié-Salpêtrière], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Ligue Nationnale Contre le Cancer, Centre de Recherche et d'Etude en Droit et Science Politique (CREDESPO), Université de Bourgogne (UB), University of Oxford, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and École Pratique des Hautes Études (EPHE)
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Mutation, Missense, lymphoma, Biology, Cell Line, Mice, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Mutant protein, Proto-Oncogene Proteins, spi-1/pu.1, pu.1, Animals, Humans, somatic mutation, Nucleotide Motifs, Lenalidomide, Transcription factor, mouse, Cell Proliferation, cll, B-Lymphocytes, Binding Sites, SPI1, Base Sequence, Proto-Oncogene Proteins c-ets, Point mutation, ETS transcription factor family, Promoter, Azepines, Triazoles, Cell biology, cell differentiation, 030104 developmental biology, Gene Expression Regulation, Oncology, 030220 oncology & carcinogenesis, Myeloid Differentiation Factor 88, Trans-Activators, acute myeloid-leukemia, Waldenstrom Macroglobulinemia, Transcription Factor Gene, Protein Binding, Transcription Factors
Abstract: The ETS-domain transcription factors divide into subfamilies based on protein similarities, DNA-binding sequences, and interaction with cofactors. They are regulated by extracellular clues and contribute to cellular processes, including proliferation and transformation. ETS genes are targeted through genomic rearrangements in oncogenesis. The PU.1/SPI1 gene is inactivated by point mutations in human myeloid malignancies. We identified a recurrent somatic mutation (Q226E) in PU.1/SPI1 in Waldenström macroglobulinemia, a B-cell lymphoproliferative disorder. It affects the DNA-binding affinity of the protein and allows the mutant protein to more frequently bind and activate promoter regions with respect to wild-type protein. Mutant SPI1 binding at promoters activates gene sets typically promoted by other ETS factors, resulting in enhanced proliferation and decreased terminal B-cell differentiation in model cell lines and primary samples. In summary, we describe oncogenic subversion of transcription factor function through subtle alteration of DNA binding leading to cellular proliferation and differentiation arrest. Significance: The demonstration that a somatic point mutation tips the balance of genome-binding pattern provides a mechanistic paradigm for how missense mutations in transcription factor genes may be oncogenic in human tumors. This article is highlighted in the In This Issue feature, p. 681
Published: 2019
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23. Comparison Between Several Integrase-defective Lentiviral Vectors Reveals Increased Integration of an HIV Vector Bearing a D167H Mutant

Author: Muhammad Qamar Saeed, Noelle Dufour, Cynthia Bartholmae, Urzula Sieranska, Malaika Knopf, Eloïse Thierry, Sylvain Thierry, Olivier Delelis, Nicolas Grandchamp, Héloïse Pilet, Philippe Ravassard, Julie Massonneau, Françoise Pflumio, Christof von Kalle, François Lachapelle, Alexis-Pierre Bemelmans, Manfred Schmidt, and Ché Serguera
Subjects: CD34+ progenitors, integrase, integration sites, lentiviral vectors, residual integration, transduction, Therapeutics. Pharmacology, RM1-950
Abstract: HIV-1 derived vectors are among the most efficient for gene transduction in mammalian tissues. As the parent virus, they carry out vector genome insertion into the host cell chromatin. Consequently, their preferential integration in transcribed genes raises several conceptual and safety issues. To address part of these questions, HIV-derived vectors have been engineered to be nonintegrating. This was mainly achieved by mutating HIV-1 integrase at functional hotspots of the enzyme enabling the development of streamlined nuclear DNA circles functional for transgene expression. Few integrase mutant vectors have been successfully tested so far for gene transfer. They are cleared with time in mitotic cells, but stable within nondividing retina cells or neurons. Here, we compared six HIV vectors carrying different integrases, either wild type or with different mutations (D64V, D167H, Q168A, K186Q+Q214L+Q216L, and RRK262-264AAH) shown to modify integrase enzymatic activity, oligomerization, or interaction with key cellular cofactor of HIV DNA integration as LEDGF/p75 or TNPO3. We show that these mutations differently affect the transduction efficiency as well as rates and patterns of integration of HIV-derived vectors suggesting their different processing in the nucleus. Surprisingly and most interestingly, we report that an integrase carrying the D167H substitution improves vector transduction efficiency and integration in both HEK-293T and primary CD34+ cells.
Published: 2014
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24. Downregulation of Glutamine Synthetase, not glutaminolysis, is responsible for glutamine addiction in Notch1‐driven acute lymphoblastic leukemia

Author: Clément Bodineau, Benjamin Uzan, Sebastian van Liempd, Jean-Max Pasquet, Juan M. Falcón-Pérez, Elodie Muzotte, H. Rezvani, Julien Calvo, Elodie Richard, María L. Toribio, Patricia Fuentes, Isabelle Redonnet-Vernhet, Silvia Terés, Marion Bouchecareilh, Mercedes Tomé, Pierre Soubeyran, Piedad del Socorro Murdoch, Benoit Rousseau, Tra Ly Nguyen, Françoise Pflumio, Marie-Julie Nokin, Oriane Galmar, Raúl V. Durán, Abdel-Majid Khatib, Muriel Priault, Centre National de la Recherche Scientifique (CNRS), Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Ministerio de Ciencia, Innovación y Universidades (MICINN). España, European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER), Agencia Estatal de Investigación (España), European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Economía y Competitividad (España), Consejo Superior de Investigaciones Científicas (España), Institut National de la Santé et de la Recherche Médicale (France), Ligue Nationale contre le Cancer (France), Université de Bordeaux, Fondation pour la Recherche Médicale, Conseil régional d'Aquitaine, Fondation ARC pour la Recherche sur le Cancer, Fonds de la Recherche Scientifique (Fédération Wallonie-Bruxelles), Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), [Nguyen,TL, Nokin,MJ, Terés,S, Bodineau,C, Galmnar,O, Durán,RV] Institut Europeen de Chimie et Biologie, INSERM U1218, Université de Bordeaux, Pessac, France. [Tomé,M, Murdoch,PDS, Durán,RV] Centro Andaluz de Biología Molecular y Medicina Regenerativa - CABIMER, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Universidad Pablo de Olavide, Seville, Spain. [Tomé,M, Khatib,AM] Angiogenesis and Cancer Microenvironment Laboratory INSERM U1029, Universite de Bordeaux, Pessac, France. [Pasquet,JM, Muzotte,E, Rezvani,HR] INSERM, BMGIC, U1035, University of Bordeaux, France. [Rousseau,B] Service Commun des Animaleries, University of Bordeaux, France. [van Liempd,S, Falcon-Perez,JM] Exosomes Laboratory and Platform of Metabolomics, CIC bioGUNE, CIBERehd, Derio, Spain. [Falcon-Perez,JM] IKERBASQUE, Basque Foundation for Science, Bilbao, Spain. [Richard,E] Institut Bergonie, INSERM U1218, University of Bordeaux, France. [Priault,M] Institut de Biochimie et Gen etique Cellulaires, CNRS UMR 5095, Université de Bordeaux, France. [Bouchecareilh,M] Bordeaux Research in Translational Oncology, INSERM U1053, Universite de Bordeaux, France. [Redonnet-Vernhet,I] Maladies Heréditaires du Métabolisme, Laboratoire de Biochimie, Hôpital Pellegrin, CHU Bordeaux, France. [Calvo,J, Uzan,B, Pflumio, F] UMR967, Inserm, CEA, Universite Paris 7, UniversitéParis 11, Fontenay-aux-Roses, France. [Fuentes,P, Toribio,ML] Centro de Biología Molecular 'Severo Ochoa', Consejo Superior de Investigaciones Científicas, Universidad Autonoma de Madrid, Spain. [Murdoch,PDS] Departamento de Bioquímica Vegetal y Biología Molecular, Universidad de Sevilla, Spain, and This work was supported by funds from the following institutions: Agencia Estatal de Investigación/European Regional Development Fund, European Union (PGC2018-096244-B-I00, SAF2016-75442-R), Ministry of Science, Innovation and Universities of Spain, Spanish National Research Council—CSIC, Institut National de la Santé et de la Recherche Médicale—INSERM, Ligue Contre le Cancer—Gironde, Université de Bordeaux, Fondation pour la Recherche Médicale, the Conseil Régional d'Aquitaine, SIRIC-BRIO, Fondation ARC and Institut Européen de Chimie et Biologie. MJN was supported by a bourse d’excellence de la Fédération Wallonie-Bruxelles (WBI) and a postdoctoral fellowship from Fondation ARC. We thank Vincent Pitard (Flow Cytometry Platform, Université de Bordeaux, France) for technical assistance in flow cytometry experiments. We thank Diana Cabrera (Metabolomics Platform, CIC bioGUNE, Spain) for technical assistance in metabolomics analysis.
Subjects: 0301 basic medicine, Male, Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor [Medical Subject Headings], Cancer Research, Glutamina, Regulación hacia abajo, [SDV]Life Sciences [q-bio], Glutamine, mTORC1, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Diana mecanicista del complejo 1 de la rapamicina, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Mice, 0302 clinical medicine, Mice, Inbred NOD, hemic and lymphatic diseases, Organisms::Eukaryota::Animals [Medical Subject Headings], Receptor, Notch1, Research Articles, RC254-282, ComputingMilieux_MISCELLANEOUS, Metabolismo, Anatomy::Cells::Blood Cells::Leukocytes::Leukocytes, Mononuclear::Lymphocytes::T-Lymphocytes [Medical Subject Headings], Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Laboratory::Animals, Inbred Strains::Mice, Inbred Strains::Mice, Inbred NOD [Medical Subject Headings], Chemistry, Gene Expression Regulation, Leukemic, Línea celular, Metabolicaddiction, Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Signal Transduction [Medical Subject Headings], Neoplasms. Tumors. Oncology. Including cancer and carcinogens, General Medicine, Precursor Cell Lymphoblastic Leukemia-Lymphoma, 3. Good health, Leukemia, Oncology, 030220 oncology & carcinogenesis, embryonic structures, cardiovascular system, Molecular Medicine, biological phenomena, cell phenomena, and immunity, Glutamato-amoníaco ligasa, T-cell acute lymphoblastic leukemia, Research Article, Signal Transduction, Receptor Notch1, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Notch::Receptor, Notch1 [Medical Subject Headings], Down-Regulation, Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Gene Expression Regulation, Neoplastic::Gene Expression Regulation, Leukemic [Medical Subject Headings], Check Tags::Male [Medical Subject Headings], Mice, Transgenic, [SDV.CAN]Life Sciences [q-bio]/Cancer, Mechanistic Target of Rapamycin Complex 1, Gene Expression Regulation, Enzymologic, Glutamine synthetase, 03 medical and health sciences, Downregulation and upregulation, Glutamate-Ammonia Ligase, Cell Line, Tumor, T‐cell acute lymphoblastic leukemia, Diseases::Neoplasms::Neoplasms by Histologic Type::Leukemia::Leukemia, Lymphoid::Precursor Cell Lymphoblastic Leukemia-Lymphoma [Medical Subject Headings], Genetics, medicine, Animals, Humans, Metabolic addiction, T-cell acutelymphoblastic leukemia, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings], Notch1, Glutaminolysis, Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Down-Regulation [Medical Subject Headings], Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Up-Regulation [Medical Subject Headings], Cell growth, Leucemia-linfoma linfoblástico de células T precursoras, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Amino Acids::Amino Acids, Basic::Glutamine [Medical Subject Headings], medicine.disease, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Ligases::Carbon-Nitrogen Ligases::Amide Synthases::Glutamate-Ammonia Ligase [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Gene Expression Regulation, Enzymologic [Medical Subject Headings], 030104 developmental biology, Apoptosis, Downregulation, metabolic addiction, Cancer research, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, Transgenic [Medical Subject Headings], sense organs, Cell line
Abstract: During glutamine sufficiency, both Notch‐positive and Notch‐negative T‐ALL cells promote glutamine catabolism, leading to mammalian target of rapamycin complex 1 (mTORC1) activation and cell growth and proliferation. However, during glutamine scarcity, only Notch‐negative T‐ALL cells can perform a metabolic adaptation by promoting glutamine synthesis. By contrast, Notch‐positive T‐ALL cells maintain glutamine catabolism during glutamine restriction, leading to glutamine addiction and mTORC1 dependency., The cellular receptor Notch1 is a central regulator of T‐cell development, and as a consequence, Notch1 pathway appears upregulated in > 65% of the cases of T‐cell acute lymphoblastic leukemia (T‐ALL). However, strategies targeting Notch1 signaling render only modest results in the clinic due to treatment resistance and severe side effects. While many investigations reported the different aspects of tumor cell growth and leukemia progression controlled by Notch1, less is known regarding the modifications of cellular metabolism induced by Notch1 upregulation in T‐ALL. Previously, glutaminolysis inhibition has been proposed to synergize with anti‐Notch therapies in T‐ALL models. In this work, we report that Notch1 upregulation in T‐ALL induced a change in the metabolism of the important amino acid glutamine, preventing glutamine synthesis through the downregulation of glutamine synthetase (GS). Downregulation of GS was responsible for glutamine addiction in Notch1‐driven T‐ALL both in vitro and in vivo. Our results also confirmed an increase in glutaminolysis mediated by Notch1. Increased glutaminolysis resulted in the activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway, a central controller of cell growth. However, glutaminolysis did not play any role in Notch1‐induced glutamine addiction. Finally, the combined treatment targeting mTORC1 and limiting glutamine availability had a synergistic effect to induce apoptosis and to prevent Notch1‐driven leukemia progression. Our results placed glutamine limitation and mTORC1 inhibition as a potential therapy against Notch1‐driven leukemia.
Published: 2021
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25. Transcriptional profiling of β-2M

Author: Maelle, Givelet, Virginie, Firlej, Bruno, Lassalle, Anne Sophie, Gille, Clementine, Lapoujade, Isabelle, Holtzman, Amandine, Jarysta, Farahd, Haghighirad, Florent, Dumont, Sébastien, Jacques, Franck, Letourneur, Françoise, Pflumio, Isabelle, Allemand, Catherine, Patrat, Nicolas, Thiounn, Jean Philippe, Wolf, Lydia, Riou, Virginie, Barraud-Lange, and Pierre, Fouchet
Subjects: Male, Mice, Adult Germline Stem Cells, Gene Expression Profiling, Stem Cells, Testis, Animals, Humans, Spermatogenesis, Spermatogonia, Transcription Factors
Abstract: Male infertility is responsible for approximately half of all cases of reproductive issues. Spermatogenesis originates in a small pool of spermatogonial stem cells (SSCs), which are of interest for therapy of infertility but remain not well defined in humans. Using multiparametric analysis of the side population (SP) phenotype and the α-6 integrin, THY1, and β-2 microglobulin cell markers, we identified a population of human primitive undifferentiated spermatogonia with the phenotype β-2 microglobulin (β-2M)
Published: 2020

26. Hypoxia favors chemoresistance in T-ALL through an HIF1α-mediated mTORC1 inhibition loop

Author: Paola Ballerini, Frédéric Mazurier, Laurent Renou, Benjamin Uzan, Sara Chabi, Irina Naguibneva, André Baruchel, Lucine Fahy, Françoise Pflumio, Julien Calvo, Marie-Laure Arcangeli, Rima Haddad, Sandrine Poglio, Thierry Leblanc, Charly Le Maout, and Arnaud Petit
Subjects: Lymphoid Neoplasia, Cell growth, Chemistry, Hematology, mTORC1, Hypoxia (medical), Mitochondrion, Mechanistic Target of Rapamycin Complex 1, medicine.disease, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Leukemia, medicine.anatomical_structure, Pharmaceutical Preparations, Drug Resistance, Neoplasm, medicine, Cancer research, Tumor Microenvironment, Humans, Glycolysis, Bone marrow, medicine.symptom, Hypoxia, PI3K/AKT/mTOR pathway
Abstract: Resistance to chemotherapy, a major therapeutic challenge in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), can be driven by interactions between leukemic cells and the microenvironment that promote survival of leukemic cells. The bone marrow, an important leukemia niche, has low oxygen partial pressures that highly participate in the regulation of normal hematopoiesis. Here we show that hypoxia inhibits T-ALL cell growth by slowing down cell cycle progression, decreasing mitochondria activity, and increasing glycolysis, making them less sensitive to antileukemic drugs and preserving their ability to initiate leukemia after treatment. Activation of the mammalian target of rapamycin (mTOR) was diminished in hypoxic leukemic cells, and treatment of T-ALL with the mTOR inhibitor rapamycin in normoxia mimicked the hypoxia effects, namely decreased cell growth and increased quiescence and drug resistance. Knocking down (KD) hypoxia-induced factor 1α (HIF-1α), a key regulator of the cellular response to hypoxia, antagonized the effects observed in hypoxic T-ALL and restored chemosensitivity. HIF-1α KD also restored mTOR activation in low O2 concentrations, and inhibiting mTOR in HIF1α KD T-ALL protected leukemic cells from chemotherapy. Thus, hypoxic niches play a protective role of T-ALL during treatments. Inhibition of HIF-1α and activation of the mTORC1 pathway may help suppress the drug resistance of T-ALL in hypoxic niches.
Published: 2020

27. Ultra-high-dose-rate FLASH and Conventional-Dose-Rate Irradiation Differentially Affect Human Acute Lymphoblastic Leukemia and Normal Hematopoiesis

Author: Sandrine Poglio, Ron Leavitt, Maud Jaccard, Thi Hong Van To, Paul-Henri Romeo, Benoit Petit, Patrik Gonçalves Jorge, Benjamin Uzan, Françoise Pflumio, Marie-Catherine Vozenin, Kristoffer Petersson, and Sara Chabi
Subjects: Organs at Risk, Cancer Research, medicine.medical_treatment, CD34, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Umbilical cord, Radiation Tolerance, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, Immunocompromised Host, Mice, 0302 clinical medicine, Medicine, Animals, Humans, Radiology, Nuclear Medicine and imaging, Progenitor cell, Radiation Injuries, Radiation, business.industry, Hematopoietic Stem Cell Transplantation, Reproducibility of Results, Radiotherapy Dosage, Total body irradiation, Genetic Profile, medicine.disease, Hematopoietic Stem Cells, Xenograft Model Antitumor Assays, Hematopoiesis, Radiation therapy, Haematopoiesis, Leukemia, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Cancer research, Stem cell, business, Whole-Body Irradiation
Abstract: Purpose Ultra-high-dose-rate FLASH radiation therapy has been shown to minimize side effects of irradiation in various organs while keeping antitumor efficacy. This property, called the FLASH effect, has caused enthusiasm in the radiation oncology community because it opens opportunities for safe dose escalation and improved radiation therapy outcome. Here, we investigated the impact of ultra-high-dose-rate FLASH versus conventional-dose-rate (CONV) total body irradiation (TBI) on humanized models of T-cell acute lymphoblastic leukemia (T-ALL) and normal human hematopoiesis. Methods and Materials We optimized the geometry of irradiation to ensure reproducible and homogeneous procedures using eRT6/Oriatron. Three T-ALL patient–derived xenografts and hematopoietic stem/progenitor cells (HSPCs) and CD34+ cells isolated from umbilical cord blood were transplanted into immunocompromised mice, together or separately. After reconstitution, mice received 4 Gy FLASH and CONV-TBI, and tumor growth and normal hematopoiesis were studied. A retrospective study of clinical and gene-profiling data previously obtained on the 3 T-ALL patient-derived xenografts was performed. Results FLASH-TBI was more efficient than CONV-TBI in controlling the propagation of 2 cases of T-ALL, whereas the third case of T-ALL was more responsive to CONV-TBI. The 2 FLASH-sensitive cases of T-ALL had similar genetic abnormalities, and a putative susceptibility imprint to FLASH-RT was found. In addition, FLASH-TBI was able to preserve some HSPC/CD34+ cell potential. Interestingly, when HSPC and T-ALL were present in the same animals, FLASH-TBI could control tumor development in most (3 of 4) of the secondary grafted animals, whereas among the mice receiving CONV-TBI, treated cells died with high leukemia infiltration. Conclusions Compared with CONV-TBI, FLASH-TBI reduced functional damage to human blood stem cells and had a therapeutic effect on human T-ALL with a common genetic and genomic profile. The validity of the defined susceptibility imprint needs to be investigated further; however, to our knowledge, the present findings are the first to show benefits of FLASH-TBI on human hematopoiesis and leukemia treatment.
Published: 2020

28. Combined G-CSF and Plerixafor enhance hematopoietic recovery of CD34

Author: Marie-Laure, Arcangeli, Philippe, Brault, Jean-Henri, Bourhis, Frédérique, Kuhnowskie, Elia, Henry, Vilma, Barroca, Serge, Koscielny, Françoise, Pflumio, and Sophie, Amsellem
Subjects: Mice, Knockout, Benzylamines, Peripheral Blood Stem Cell Transplantation, Antigens, CD34, Mice, SCID, Cyclams, Hematopoietic Stem Cell Mobilization, Mice, Heterocyclic Compounds, Mice, Inbred NOD, Granulocyte Colony-Stimulating Factor, Peripheral Blood Stem Cells, Animals, Heterografts, Humans
Abstract: Transplantable CD34
Published: 2020

29. HOXC4 homeoprotein efficiently expands human hematopoietic stem cells and triggers similar molecular alterations as HOXB4

Author: Céline Auvray, Andrée Delahaye, Françoise Pflumio, Rima Haddad, Sophie Amsellem, Ayda Miri-Nezhad, Loïc Broix, Azzedine Yacia, Frédérique Bulle, Serge Fichelson, and Isabelle Vigon
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Abstract: Background Expansion of hematopoietic stem cells represents an important objective for improving cell and gene therapy protocols. Retroviral transduction of the HoxB4 homeogene in mouse and human hematopoietic stem cells and hematopoietic progenitors is known to promote the cells’ expansion. A safer approach consists in transferring homeobox proteins into hematopoietic stem cells taking advantage of the natural ability of homeoproteins to cross cell membranes. Thus, HOXB4 protein transfer is operative for expanding human hematopoietic cells, but such expansion needs to be improved.Design and Methods To that aim, we evaluated the effects of HOXC4, a protein encoded by a HOXB4 paralog gene, by co-culturing HOXC4-producing stromal cells with human CD34+ hematopoietic cells. Numbers of progenitors and stem cells were assessed by in vitro cloning assays and injection into immuno-deficient mice, respectively. We also looked for activation or inhibition of target downstream gene expression.Results We show that the HOXC4 homeoprotein expands human hematopoietic immature cells by 3 to 6 times ex vivo and significantly improves the level of in vivo engraftment. Comparative transcriptome analysis of CD34+ cells subjected or not to HOXB4 or HOXC4 demonstrated that both homeoproteins regulate the same set of genes, some of which encode key hematopoietic factors and signaling molecules. Certain molecules identified herein are factors reported to be involved in stem cell fate or expansion in other models, such as MEF2C, EZH2, DBF4, DHX9, YPEL5 and Pumilio.Conclusions The present study may help to identify new HOX downstream key factors potentially involved in hematopoietic stem cell expansion or in leukemogenesis.
Published: 2012
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30. Clinical relevance of tumor cells with stem-like properties in pediatric brain tumors.

Author: Cécile Thirant, Barbara Bessette, Pascale Varlet, Stéphanie Puget, Josette Cadusseau, Silvina Dos Reis Tavares, Jeanne-Marie Studler, David Carlos Silvestre, Aurélie Susini, Chiara Villa, Catherine Miquel, Alexandra Bogeas, Anne-Laure Surena, Amélia Dias-Morais, Nadine Léonard, Françoise Pflumio, Ivan Bièche, François D Boussin, Christian Sainte-Rose, Jacques Grill, Catherine Daumas-Duport, Hervé Chneiweiss, and Marie-Pierre Junier
Subjects: Medicine, Science
Abstract: BackgroundPrimitive brain tumors are the leading cause of cancer-related death in children. Tumor cells with stem-like properties (TSCs), thought to account for tumorigenesis and therapeutic resistance, have been isolated from high-grade gliomas in adults. Whether TSCs are a common component of pediatric brain tumors and are of clinical relevance remains to be determined.Methodology/principal findingsTumor cells with self-renewal properties were isolated with cell biology techniques from a majority of 55 pediatric brain tumors samples, regardless of their histopathologies and grades of malignancy (57% of embryonal tumors, 57% of low-grade gliomas and neuro-glial tumors, 70% of ependymomas, 91% of high-grade gliomas). Most high-grade glioma-derived oncospheres (10/12) sustained long-term self-renewal akin to neural stem cells (>7 self-renewals), whereas cells with limited renewing abilities akin to neural progenitors dominated in all other tumors. Regardless of tumor entities, the young age group was associated with self-renewal properties akin to neural stem cells (P = 0.05, chi-square test). Survival analysis of the cohort showed an association between isolation of cells with long-term self-renewal abilities and a higher patient mortality rate (P = 0.013, log-rank test). Sampling of low- and high-grade glioma cultures showed that self-renewing cells forming oncospheres shared a molecular profile comprising embryonic and neural stem cell markers. Further characterization performed on subsets of high-grade gliomas and one low-grade glioma culture showed combination of this profile with mesenchymal markers, the radio-chemoresistance of the cells and the formation of aggressive tumors after intracerebral grafting.Conclusions/significanceIn brain tumors affecting adult patients, TSCs have been isolated only from high-grade gliomas. In contrast, our data show that tumor cells with stem cell-like or progenitor-like properties can be isolated from a wide range of histological sub-types and grades of pediatric brain tumors. They suggest that cellular mechanisms fueling tumor development differ between adult and pediatric brain tumors.
Published: 2011
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31. ETO2-GLIS2 Hijacks Transcriptional Complexes to Drive Cellular Identity and Self-Renewal in Pediatric Acute Megakaryoblastic Leukemia

Author: Arnaud Petit, Françoise Pflumio, Cécile Thirant, Cécile K. Lopez, Sébastien Malinge, Hana Raslova, Aurelie Siret, Olivier A. Bernard, Clarisse Thiollier, Cathy Ignacimouttou, Mehdi Khaled, M'Boyba Diop, Jürg Schwaller, William Vainchenker, John D. Crispino, Paola Ballerini, Guy Leverger, Ce ' Line Lefebvre, Philippe Rameau, Benjamin T. Kile, Catherine Carmichael, Lou Le Mouel, Eric Soler, Phillipe Dessen, Thomas Mercher, Zakia Aid, Julie Riviere, Nathalie Droin, Christian Wichmann, Camille Lobry, Hématopoïèse normale et pathologique ( U1170 Inserm ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Plateforme imagerie et cytométrie ( PFIC ), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse ( AMMICa ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Ondes et Imagerie ( O&I ), Laboratoire de Mécanique et d'Acoustique [Marseille] ( LMA ), Centre National de la Recherche Scientifique ( CNRS ) -Aix Marseille Université ( AMU ) -Ecole Centrale de Marseille ( ECM ) -Centre National de la Recherche Scientifique ( CNRS ) -Aix Marseille Université ( AMU ) -Ecole Centrale de Marseille ( ECM ), Hôpital Trousseau, CHRU Tours, CHU Trousseau [APHP], Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Gustave Roussy ( IGR ), Centre de génétique et de physiologie moléculaire et cellulaire ( CGPhiMC ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Northwestern University Chicago, Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ), Plateforme de génomique, Laboratoire des Adaptations Physiologiques aux Activités Physiques ( LAPHAP ), Université de Poitiers, Aix Marseille Université ( AMU ) -Ecole Centrale de Marseille ( ECM ) -Centre National de la Recherche Scientifique ( CNRS ) -Aix Marseille Université ( AMU ) -Ecole Centrale de Marseille ( ECM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), and Université de Lyon-Université de Lyon
Subjects: Transcriptional Activation, 0301 basic medicine, Cancer Research, Oncogene Proteins, Fusion, ChIP, Biology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mice, 03 medical and health sciences, Acute megakaryoblastic leukemia, Transcriptional Regulator ERG, GLIS2, Downregulation and upregulation, Leukemia, Megakaryoblastic, Acute, Transcription (biology), medicine, Animals, Humans, GATA1 Transcription Factor, Child, Enhancer, Gene, Transcription factor, transcription factor, CBFA2T3, AMKL, leukemia, Cell Differentiation, GLIS, medicine.disease, Leukemia, pediatric, Enhancer Elements, Genetic, 030104 developmental biology, Oncology, ERG, CRISPR, Cancer research, enhancer
Abstract: International audience; Chimeric transcription factors are a hallmark of human leukemia, but the molecular mechanisms by which they block differentiation and promote aberrant self-renewal remain unclear. Here, we demonstrate that the ETO2-GLIS2 fusion oncoprotein, which is found in aggressive acute megakaryoblastic leukemia, confers megakaryocytic identity via the GLIS2 moiety while both ETO2 and GLIS2 domains are required to drive increased self-renewal properties. ETO2-GLIS2 directly binds DNA to control transcription of associated genes by upregulation of expression and interaction with the ETS-related ERG protein at enhancer elements. Importantly, specific interference with ETO2-GLIS2 oligomerization reverses the transcriptional activation at enhancers and promotes megakaryocytic differentiation, providing a relevant interface to target in this poor-prognosis pediatric leukemia.
Published: 2017
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32. Desperately seeking a home marrow niche for T-cell acute lymphoblastic leukaemia

Author: Julien Calvo, Lucine Fahy, Benjamin Uzan, Françoise Pflumio, Stabilité génétique, cellules souches et radiations (SGCSR (U_1274 / UMR_E_008)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), CCSD, Accord Elsevier, and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Paris (UP)
Subjects: 0301 basic medicine, Cancer Research, [SDV]Life Sciences [q-bio], Niche, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, 03 medical and health sciences, 0302 clinical medicine, Bone Marrow, Genetics, Hematologic malignancy, medicine, Tumor Microenvironment, Animals, Humans, Progenitor cell, Molecular Biology, Acute leukemia, business.industry, T-cell acute lymphoblastic leukaemia, medicine.disease, [SDV] Life Sciences [q-bio], Leukemia, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Molecular Medicine, Hematopoietic progenitor cells, Bone marrow, business
Abstract: T-cell acute leukemia is a hematologic malignancy that results from the progressive acquisition of genomic abnormalities in T-cell progenitors/precursors. T-ALL is commonly thought to originate from the thymus albeit recent literature describes the possible acquisition of the first oncogenic hits in hematopoietic progenitor cells of the bone marrow (BM). The journey of T-ALL from its arising to full blown expansion meets different microenvironments, including the BM in which leukemic cells settle down early after the disease spreading. We take advantage of recent literature to give an overview of important cells and factors that participate in T-ALL, especially in the BM, arguing in favor of a home marrow niche for this rare leukemia.
Published: 2019
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33. Ontogenic changes in hematopoietic hierarchy determine pediatric specificity and disease phenotype in fusion oncogene-driven myeloid leukemia

Author: Cécile K. Lopez, Marie Laure Arcangeli, Eric Delabesse, Sébastien Malinge, Alexandre Fagnan, Isabelle Godin, Franco Locatelli, Françoise Pflumio, Fabien Boudia, Cécile Thirant, Muriel Gaudry, Vaia Stavropoulou, Arnaud Petit, Claus Nerlov, Nathalie Droin, Riccardo Masetti, Paola Ballerini, Zakia Aid, Berthold Göttgens, Olivier Bernard, Sarah Kinston, Erika Brunet, Hélène Lapillonne, Loelia Babin, Juerg Schwaller, Antoine H.F.M. Peters, Elie Robert, Yann Lécluse, Bastien Job, Chrystele Bilhou-Nabera, Jean-Luc Villeval, Camille Lobry, William Vainchenker, Thomas Mercher, Esteve Noguera, M'Boyba Diop, Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [APHP], Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Stabilité génétique, Cellules Souches et Radiations (SCSR (U_967)), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de Bioinformatique [Gustave Roussy], Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Bases fondamentales et stratégies nouvelles en cancérologie (BFSNC - IFR54), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Régulation et dynamique des génomes, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Santa Lucia Foundation, IRCSS, Rome, University of Oxford [Oxford], Images et Modèles, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Cambridge [UK] (CAM), Service Procédés et Innovations Industriels (SPII), eRcane, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique des tumeurs (U985), Institut Gustave Roussy (IGR)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche et d'Etude en Droit et Science Politique (CREDESPO), Université de Bourgogne (UB), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lopez C.K., Noguera E., Stavropoulou V., Robert E., Aid Z., Ballerini P., Bilhou-Nabera C., Lapillonne H., Boudia F., Thirant C., Fagnan A., Arcangeli M.-L., Kinston S.J., Diop M., Job B., Lecluse Y., Brunet E., Babin L., Villeval J.L., Delabesse E., Peters A.H.F.M., Vainchenker W., Gaudry M., Masetti R., Locatelli F., Malinge S., Nerlov C., Droin N., Lobry C., Godin I., Bernard O.A., Gottgens B., Petit A., Pflumio F., Schwaller J., Mercher T., Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire d'Hématologie [AP-HP Hôpital Armand Trousseau], Cellules Souches et Radiations (SCSR (U967 / UMR-E_008)), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Brunet, Erika [0000-0002-1726-4673], Malinge, Sébastien [0000-0002-9533-7778], Droin, Nathalie [0000-0002-6099-5324], Godin, Isabelle [0000-0001-8577-8388], Göttgens, Berthold [0000-0001-6302-5705], Schwaller, Juerg [0000-0001-8616-0096], Mercher, Thomas [0000-0003-1552-087X], Apollo - University of Cambridge Repository, Centre de Psychiatrie et Neurosciences (U894), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Oxford, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Myeloid, Oncogene Proteins, Fusion, Oncogene Proteins, Fusion gene, Mice, 0302 clinical medicine, AML, CEBPA, GENOMIC ALTERATIONS, Tumor Cells, Cultured, TRANSCRIPTION FACTOR, RNA-SEQ, Child, ComputingMilieux_MISCELLANEOUS, GENE-EXPRESSION, Age Factors, Myeloid leukemia, GATA1, 3. Good health, Leukemia, Myeloid, Acute, Leukemia, Haematopoiesis, medicine.anatomical_structure, DIFFERENTIATION, Oncology, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Child, Preschool, 030220 oncology & carcinogenesis, Female, Adolescent, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, children, ACUTE MEGAKARYOBLASTIC LEUKEMIA, transcription factors, medicine, Animals, Humans, FETAL, pediatric acute myeloid leukemia, LINEAGE COMMITMENT, Infant, medicine.disease, STEM-CELL, SELF-RENEWAL, 030104 developmental biology, Cancer research, Neoplasm Transplantation
Abstract: Fusion oncogenes are prevalent in several pediatric cancers, yet little is known about the specific associations between age and phenotype. We observed that fusion oncogenes, such as ETO2–GLIS2, are associated with acute megakaryoblastic or other myeloid leukemia subtypes in an age-dependent manner. Analysis of a novel inducible transgenic mouse model showed that ETO2–GLIS2 expression in fetal hematopoietic stem cells induced rapid megakaryoblastic leukemia whereas expression in adult bone marrow hematopoietic stem cells resulted in a shift toward myeloid transformation with a strikingly delayed in vivo leukemogenic potential. Chromatin accessibility and single-cell transcriptome analyses indicate ontogeny-dependent intrinsic and ETO2–GLIS2-induced differences in the activities of key transcription factors, including ERG, SPI1, GATA1, and CEBPA. Importantly, switching off the fusion oncogene restored terminal differentiation of the leukemic blasts. Together, these data show that aggressiveness and phenotypes in pediatric acute myeloid leukemia result from an ontogeny-related differential susceptibility to transformation by fusion oncogenes. Significance: This work demonstrates that the clinical phenotype of pediatric acute myeloid leukemia is determined by ontogeny-dependent susceptibility for transformation by oncogenic fusion genes. The phenotype is maintained by potentially reversible alteration of key transcription factors, indicating that targeting of the fusions may overcome the differentiation blockage and revert the leukemic state. See related commentary by Cruz Hernandez and Vyas, p. 1653. This article is highlighted in the In This Issue feature, p. 1631
Published: 2019
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34. Stem Cell Leukemia: how a TALented actor can go awry on the hematopoietic stage

Author: João T. Barata, Nádia C. Correia, Marie-Laure Arcangeli, and Françoise Pflumio
Subjects: 0301 basic medicine, Cancer Research, Leukemia, T-Cell, Carcinogenesis, T-Cell Acute Lymphocytic Leukemia Protein 1, Biology, 03 medical and health sciences, Proto-Oncogene Proteins, Basic Helix-Loop-Helix Transcription Factors, medicine, Humans, Transcription factor, Hematopoietic stem cell, Hematology, medicine.disease, 3. Good health, Haematopoiesis, Leukemia, 030104 developmental biology, medicine.anatomical_structure, Oncology, Immunology, Neoplastic Stem Cells, Ectopic expression, Stem cell, Neuroscience, TAL1
Abstract: TAL1/SCL/TCL5 is a critical transcription factor for hematopoietic stem cell maintenance and regulation of early hematopoiesis. However, aberrant expression of TAL1 in committed T-cell precursors is also directly implicated in the development of T-cell leukemia. Roughly 25 years ago TAL1 was identified in early hematopoietic cells and involved in leukemia. Here, we review the wealth of knowledge gained since then on its physiological roles and mechanisms by which TAL1 ectopic expression contributes to leukemogenesis. We emphasize recent findings that shed light into the intricacies of TAL1 (epi)genetic regulation and the transcription network orchestrated by this major T-cell oncogene. Importantly, an exciting time is coming when data using the mechanistic knowledge accumulated on TAL1 may be used to develop novel anti-leukemia targeted therapies.
Published: 2016
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35. Speed of leukemia development and genetic diversity in xenograft models of T cell acute lymphoblastic leukemia

Author: André Baruchel, Judith Landman-Parker, Daniel Lewandowski, Paola Ballerini, Jean Soulier, Thierry Leblanc, Sandrine Poglio, Audrey Gros, Elodie Laharanne, Julien Calvo, Françoise Pflumio, Aurélie Caye, and Emmanuelle Clappier
Subjects: 0301 basic medicine, Human leukemia, Time Factors, T cell, Lymphoblastic Leukemia, Transplantation, Heterologous, Mice, Nude, Antigens, CD34, Mice, Transgenic, Mice, SCID, Newly diagnosed, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, clonal selection, Genetic Heterogeneity, Mice, Young Adult, 03 medical and health sciences, Mice, Inbred NOD, hemic and lymphatic diseases, Cell Line, Tumor, medicine, Animals, Humans, xenograft, Child, Translational oncology, business.industry, Genetic Variation, leukemia initiating cells, medicine.disease, Molecular biology, 3. Good health, Leukemia, 030104 developmental biology, medicine.anatomical_structure, Oncology, Immunology, Disease Progression, Heterografts, Genetic selection, CD34, T-ALL, business, Neoplasm Transplantation, Research Paper
Abstract: // Sandrine Poglio 1, 2, 3, 4 , Daniel Lewandowski 2, 3, 4, 5 , Julien Calvo 1, 2, 3, 4 , Aurelie Caye 6, 7 , Audrey Gros 8, 9 , Elodie Laharanne 8, 9 , Thierry Leblanc 10 , Judith Landman-Parker 11 , Andre Baruchel 10 , Jean Soulier 6, 12, 13 , Paola Ballerini 1, 2, 3, 4, 11 , Emmanuelle Clappier 6, 12, 13 , Francoise Pflumio 1, 2, 3, 4 1 Commissariat a l’Energie Atomique et aux Energies Alternatives (CEA), DSV-IRCM-SCSR-LSHL, UMR 967, Fontenay-aux-Roses, France 2 INSERM, U967, Fontenay-aux-Roses, France 3 Universite Paris Diderot, Sorbonne Paris Cite, UMR 967, Fontenay-aux-Roses, France 4 Universite Paris-Sud, UMR 967, Fontenay-aux-Roses, France 5 CEA, DSV-IRCM-SCSR-LRTS, UMR 967, Fontenay-aux-Roses, France 6 Universite Paris Diderot, Paris, France 7 Assistance Publique-Hopitaux de Paris (AP-HP), Departement de Genetique, UF de Genetique Moleculaire, Hopital Robert Debre Paris, France 8 INSERM, UMR1053 Bordeaux Research in Translational Oncology (BaRITOn), Bordeaux, France 9 Universite de Bordeaux, Bordeaux, France 10 AP-HP, Service d’hematologie Pediatrique, Hopital Robert Debre, Paris, France 11 AP-HP, Service d’hematologie Pediatrique, Hopital Armand Trousseau, Paris, France 12 AP-HP, Laboratoire d’Hematologie, Hopital Saint-Louis, Paris, France 13 Team Genome and Cancer, U944 INSERM, Paris, France Correspondence to: Francoise Pflumio, email: francoise.pflumio@cea.fr Sandrine Poglio, email: sandrine.poglio@u-bordeaux.fr Keywords: T-ALL, leukemia initiating cells, clonal selection, CD34, xenograft Received: June 29, 2015 Accepted: April 22, 2016 Published: May 12, 2016 ABSTRACT T cell acute lymphoblastic leukemia (T-ALL) develops through accumulation of multiple genomic alterations within T-cell progenitors resulting in clonal heterogeneity among leukemic cells. Human T-ALL xeno-transplantation in immunodeficient mice is a gold standard approach to study leukemia biology and we recently uncovered that the leukemia development is more or less rapid depending on T-ALL sample. The resulting human leukemia may arise through genetic selection and we previously showed that human T-ALL development in immune-deficient mice is significantly enhanced upon CD7 + /CD34 + leukemic cell transplantations. Here we investigated the genetic characteristics of CD7 + /CD34 + and CD7 + /CD34 − cells from newly diagnosed human T-ALL and correlated it to the speed of leukemia development. We observed that CD7 + /CD34 + or CD7 + /CD34 − T-ALL cells that promote leukemia within a short-time period are genetically similar, as well as xenograft-derived leukemia resulting from both cell fractions. In the case of delayed T-ALL growth CD7 + /CD34 + or CD7 + /CD34 − cells were either genetically diverse, the resulting xenograft leukemia arising from different but branched subclones present in the original sample, or similar, indicating decreased fitness to mouse micro-environment. Altogether, our work provides new information relating the speed of leukemia development in xenografts to the genetic diversity of T-ALL cell compartments.
Published: 2016
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36. UTX inhibition as selective epigenetic therapy against TAL1-driven T-cell acute lymphoblastic leukemia

Author: Marjorie Brand, Christopher J. Porter, F. Jeffrey Dilworth, Fengtao Dai, Carmen G. Palii, Aissa Benyoucef, Patricia Rakopoulos, Françoise Pflumio, Josée Hébert, Theodore J. Perkins, Suming Huang, Chaochen Wang, Véronique Tremblay, Kai Ge, Jean-François Couture, Kulwant Singh, and Alphonse Chu
Subjects: 0301 basic medicine, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Epigenesis, Genetic, 03 medical and health sciences, Histone demethylation, hemic and lymphatic diseases, Cell Line, Tumor, Proto-Oncogene Proteins, Coactivator, Basic Helix-Loop-Helix Transcription Factors, Genetics, medicine, Humans, Epigenetics, T-Cell Acute Lymphocytic Leukemia Protein 1, Histone Demethylases, biology, Nuclear Proteins, Genetic Therapy, medicine.disease, 3. Good health, Gene Expression Regulation, Neoplastic, Leukemia, 030104 developmental biology, Histone, Gene Knockdown Techniques, biology.protein, Cancer research, Demethylase, Epigenetic therapy, Research Paper, Developmental Biology, TAL1
Abstract: T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous group of hematological tumors composed of distinct subtypes that vary in their genetic abnormalities, gene expression signatures, and prognoses. However, it remains unclear whether T-ALL subtypes differ at the functional level, and, as such, T-ALL treatments are uniformly applied across subtypes, leading to variable responses between patients. Here we reveal the existence of a subtype-specific epigenetic vulnerability in T-ALL by which a particular subgroup of T-ALL characterized by expression of the oncogenic transcription factor TAL1 is uniquely sensitive to variations in the dosage and activity of the histone 3 Lys27 (H3K27) demethylase UTX/KDM6A. Specifically, we identify UTX as a coactivator of TAL1 and show that it acts as a major regulator of the TAL1 leukemic gene expression program. Furthermore, we demonstrate that UTX, previously described as a tumor suppressor in T-ALL, is in fact a pro-oncogenic cofactor essential for leukemia maintenance in TAL1-positive (but not TAL1-negative) T-ALL. Exploiting this subtype-specific epigenetic vulnerability, we propose a novel therapeutic approach based on UTX inhibition through in vivo administration of an H3K27 demethylase inhibitor that efficiently kills TAL1-positive primary human leukemia. These findings provide the first opportunity to develop personalized epigenetic therapy for T-ALL patients.
Published: 2016
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37. Fratricide-resistant CD1a-specific CAR T cells for the treatment of cortical T-cell acute lymphoblastic leukemia

Author: María L. Toribio, José Luis Fuster, Clara Bueno, Julien Calvo, Francisco Gutierrez-Agüera, Jan Cools, Benjamin Uzan, Manuel Ramírez-Orellana, Françoise Pflumio, Sara González-García, Talia Velasco-Hernandez, Montserrat Torrebadell, Matteo Libero Baroni, O. Blanch-Lombarte, Pablo Menendez, Diego Sánchez-Martínez, Julia G. Prado, Jordi Juncà, Mireia Camós, and Heleia Roca-Ho
Subjects: Immunobiology and Immunotherapy, MONOCLONAL-ANTIBODY, T-Lymphocytes, medicine.medical_treatment, CD34, CHILDREN, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Biochemistry, Jurkat cells, Immunotherapy, Adoptive, Antigens, CD1, Jurkat Cells, Mice, 0302 clinical medicine, hemic and lymphatic diseases, Medicine, CYTOGENETIC ABNORMALITIES, 0303 health sciences, Receptors, Chimeric Antigen, integumentary system, THYMECTOMY, SAFETY SWITCH, HUMAN THYMUS, Hematology, CHIMERIC ANTIGEN RECEPTOR, 3. Good health, medicine.anatomical_structure, IMMUNE FUNCTION, Life Sciences & Biomedicine, EXPRESSION, T cell, Immunology, MESENCHYMAL STEM-CELLS, 03 medical and health sciences, Antigen, Animals, Humans, Progenitor cell, 030304 developmental biology, Science & Technology, business.industry, Cell Biology, Immunotherapy, Xenograft Model Antitumor Assays, Chimeric antigen receptor, Cell culture, Drug Resistance, Neoplasm, Cancer research, business, Automobiles, 030215 immunology
Abstract: Relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) has a dismal outcome, and no effective targeted immunotherapies for T-ALL exist. The extension of chimeric antigen receptor (CAR) T cells (CARTs) to T-ALL remains challenging because the shared expression of target antigens between CARTs and T-ALL blasts leads to CART fratricide. CD1a is exclusively expressed in cortical T-ALL (coT-ALL), a major subset of T-ALL, and retained at relapse. This article reports that the expression of CD1a is mainly restricted to developing cortical thymocytes, and neither CD34+ progenitors nor T cells express CD1a during ontogeny, confining the risk of on-target/off-tumor toxicity. We thus developed and preclinically validated a CD1a-specific CAR with robust and specific cytotoxicity in vitro and antileukemic activity in vivo in xenograft models of coT-ALL, using both cell lines and coT-ALL patient-derived primary blasts. CD1a-CARTs are fratricide resistant, persist long term in vivo (retaining antileukemic activity in re-challenge experiments), and respond to viral antigens. Our data support the therapeutic and safe use of fratricide-resistant CD1a-CARTs for relapsed/refractory coT-ALL. ispartof: BLOOD vol:133 issue:21 pages:2291-2304 ispartof: location:United States status: published
Published: 2018

38. Single-cell analysis reveals the continuum of human lympho-myeloid progenitor cells

Author: Stephen Taylor, Emmanouela Repapi, Catherine Porcher, Berthold Göttgens, Paresh Vyas, Dimitris Karamitros, Zahra Aboukhalil, Julien Calvo, Andreas Reinisch, Bilyana Stoilova, Françoise Pflumio, Marina Samitsch, Emmanuelle Six, Fiona K. Hamey, Lynn Quek, Jessica Doondeea, Nicolas Goardon, Ravindra Majeti, Batchimeg Usukhbayar, Georg W. Otto, The Weatherall Institute of Molecular Medicine, University of Oxford [Oxford], University of Cambridge [UK] (CAM), Stanford University School of Medicine [CA, USA], Stabilité génétique, Cellules Souches et Radiations (SCSR (U_967)), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Department of Cancer Biology and Genetics, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), University of Oxford, Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Hamey, Fiona [0000-0001-7299-2860], Otto, Georg [0000-0002-3929-948X], Repapi, Emmanouela [0000-0001-8085-0731], Pflumio, Francoise [0000-0001-8995-596X], Vyas, Paresh [0000-0003-3931-0914], Apollo - University of Cambridge Repository, and Savelli, Bruno
Subjects: 0301 basic medicine, Myeloid, Cellular differentiation, [SDV]Life Sciences [q-bio], education, Immunology, Transplantation, Heterologous, Cell Separation, Biology, 03 medical and health sciences, Mice, medicine, Immunology and Allergy, Animals, Humans, Cell Lineage, Progenitor cell, health care economics and organizations, Cells, Cultured, Myeloid Progenitor Cells, Progenitor, Gene Expression Profiling, Hematopoietic Stem Cell Transplantation, Cell Differentiation, Lymphoid Progenitor Cells, Cell biology, 3. Good health, Hematopoiesis, [SDV] Life Sciences [q-bio], Transplantation, Haematopoiesis, 030104 developmental biology, medicine.anatomical_structure, Stem cell, Single-Cell Analysis
Abstract: International audience; The hierarchy of human hemopoietic progenitor cells that produce lymphoid and granulocytic–monocytic (myeloid) lineages is unclear. Multiple progenitor populations produce lymphoid and myeloid cells, but they remain incompletely characterized. Here we demonstrated that lympho-myeloid progenitor populations in cord blood — lymphoid-primed multi-potential progenitors (LMPPs), granulocyte-macrophage progenitors (GMPs) and multi-lymphoid progenitors (MLPs) — were functionally and transcriptionally distinct and heterogeneous at the clonal level, with progenitors of many different functional potentials present. Although most progenitors had the potential to develop into only one mature cell type (‘uni-lineage potential’), bi- and rarer multi-lineage progenitors were present among LMPPs, GMPs and MLPs. Those findings, coupled with single-cell expression analyses, suggest that a continuum of progenitors execute lymphoid and myeloid differentiation, rather than only uni-lineage progenitors’ being present downstream of stem cells.
Published: 2018
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39. The SCL/TAL1 Transcription Factor Represses the Stress Protein DDiT4/REDD1 in Human Hematopoietic Stem/Progenitor Cells

Author: Marie-Laure Arcangeli, Maryam Mehrpour, Julien Calvo, Sophie Amsellem, Françoise Pflumio, Irina Naguibneva, Aissa Benyoucef, Anita van den Heuvel, Eric Soler, Jérôme Larghero, Laurent Renou, and Cell biology
Subjects: Transfection, Mice, Mice, Inbred NOD, Proto-Oncogene Proteins, Basic Helix-Loop-Helix Transcription Factors, T Cell Transcription Factor 1, Animals, Humans, Progenitor cell, Heat-Shock Proteins, T-Cell Acute Lymphocytic Leukemia Protein 1, PI3K/AKT/mTOR pathway, Gene knockdown, DDIT4, biology, Stem Cells, Intracellular Signaling Peptides and Proteins, Cell Biology, Hematopoietic Stem Cells, Haematopoiesis, biology.protein, Cancer research, Molecular Medicine, Stem cell, Chromatin immunoprecipitation, Transcription Factors, Developmental Biology, TAL1
Abstract: Hematopoietic stem/progenitor cells (HSPCs) are regulated through numerous molecular mechanisms that have not been interconnected. The transcription factor stem cell leukemia/T-cell acute leukemia 1 (TAL1) controls human HSPC but its mechanism of action is not clarified. In this study, we show that knockdown (KD) or short-term conditional over-expression (OE) of TAL1 in human HSPC ex vivo, respectively, blocks and maintains hematopoietic potentials, affecting proliferation of human HSPC. Comparative gene expression analyses of TAL1/KD and TAL1/OE human HSPC revealed modifications of cell cycle regulators as well as previously described TAL1 target genes. Interestingly an inverse correlation between TAL1 and DNA damage-induced transcript 4 (DDiT4/REDD1), an inhibitor of the mammalian target of rapamycin (mTOR) pathway, is uncovered. Low phosphorylation levels of mTOR target proteins in TAL1/KD HSPC confirmed an interplay between mTOR pathway and TAL1 in correlation with TAL1-mediated effects of HSPC proliferation. Finally chromatin immunoprecipitation experiments performed in human HSPC showed that DDiT4 is a direct TAL1 target gene. Functional analyses showed that TAL1 represses DDiT4 expression in HSPCs. These results pinpoint DDiT4/REDD1 as a novel target gene regulated by TAL1 in human HSPC and establish for the first time a link between TAL1 and the mTOR pathway in human early hematopoietic cells. Stem Cells 2015;33:2268–2279
Published: 2015
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40. Saracatinib impairs maintenance of human T-ALL by targeting the LCK tyrosine kinase in cells displaying high level of lipid rafts

Author: Géraldine Lucchi, Benjamin Uzan, Françoise Pflumio, Anne Buffière, Laurent Delva, Jean-Noël Bastie, Ronan Quéré, Paola Ballerini, Laetitia Saint-Paul, Théo Accogli, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bourgogne Franche-Comté [COMUE] (UBFC), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Montpellier (UM), Plate-forme Protéomique CLIPP - Clinical and Innovation Proteomic Platform [Dijon] (CLIPP), Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)-Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon] (ICMUB), Centre National de la Recherche Scientifique (CNRS)-Université de Bourgogne (UB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Bourgogne (UB)-Institut de Chimie du CNRS (INC), Laboratoire de Recherche sur les Cellules Souches Hématopoiétiques et Leucémiques (LSHL), Université Paris Diderot - Paris 7 (UPD7)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)-Université de Montpellier (UM), Université de Franche-Comté (UFC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Technologie de Belfort-Montbeliard (UTBM)-Université de Franche-Comté (UFC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Technologie de Belfort-Montbeliard (UTBM)-Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon] (ICMUB), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP]-Sorbonne Université (SU), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon] (ICMUB), Université de Bourgogne (UB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Bourgogne (UB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École Pratique des Hautes Études (EPHE), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Cancer Research, Reactive oxygen species metabolism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, 03 medical and health sciences, chemistry.chemical_compound, Preclinical research, Mice, Membrane Microdomains, Cell Line, Tumor, Animals, Humans, Acute lymphocytic leukaemia, Benzodioxoles, Lipid raft, ComputingMilieux_MISCELLANEOUS, Membrane potential, Membrane Potential, Mitochondrial, Saracatinib, Chemistry, Hematology, Xenograft Model Antitumor Assays, Disease Models, Animal, 030104 developmental biology, Oncology, Cell culture, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), Cancer research, Neoplastic Stem Cells, Quinazolines, Reactive Oxygen Species, Tyrosine kinase
Abstract: International audience
Published: 2017
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41. Bone marrow hematons: An access point to the human hematopoietic niche

Author: Rima Haddad, Bruno Pereira, Nathalie Boiret-Dupré, Frédérique Dubois-Galopin, Richard Lemal, Céline Bourgne, Marc G. Berger, Céline Lambert, Juliette Berger, Alexandre Janel, Françoise Pflumio, Sara Chabi, Jacques-Olivier Bay, Charlotte Bothorel, Pierre Déchelotte, Eric Hermet, Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Service d’Hématologie Biologique [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Laboratoire d'Hématologie [Purpan], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Service d'Anatomie Pathologique [CHU Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Service d’Hématologie Clinique Adulte et de Thérapie Cellulaire, Inserm U967, Fontenay‐aux‐Roses cedex, France, service de Biostatistiques, DRCI, Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: Adult, Male, 0301 basic medicine, Myeloid, Adolescent, medicine.medical_treatment, Transplantation, Heterologous, CD34, Bone Marrow Cells, Stem cell factor, Cell Communication, Hematopoietic stem cell transplantation, Biology, Models, Biological, Mice, Young Adult, 03 medical and health sciences, Bone Marrow, medicine, Animals, Humans, Progenitor cell, ComputingMilieux_MISCELLANEOUS, Aged, Aged, 80 and over, Microscopy, Confocal, Hematopoietic Stem Cell Transplantation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Middle Aged, Flow Cytometry, Hematopoietic Stem Cells, Healthy Volunteers, Hematopoiesis, Cell biology, Microscopy, Electron, Haematopoiesis, 030104 developmental biology, medicine.anatomical_structure, Immunology, Female, Bone marrow, Stem cell
Abstract: To understand the complex interactions between hematopoietic stem cells and the bone marrow niche, a human experimental model is needed. Our hypothesis is that hematons are an appropriate ex vivo model of human bone marrow. We analyzed the hierarchical hematopoietic cell content and the tissue organization of single hematons from healthy donors. Most (>90%) hematons contained precursors of all cell lineages, myeloid progenitors, and LTC-ICs without preferential commitment. Approximately, half of the hematons could generate significant levels of lympho-myeloid hematopoiesis after transplantation in an NSG mouse model, despite the low absolute numbers of transplanted CD34+ cells. Mesenchymal STRO-1+ and/or CD271+ cells formed a critical network that preserved hematon cohesion, and STRO-1+ cells colocalized with most hematopoietic CD34+ cells (68%). We observed an influence of age and gender. These structures represent a particularly attractive model for studying the homeostasis of the bone marrow niche and pathological changes that occur during diseases.
Published: 2017
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42. PUMILIO/FOXP1 signaling drives expansion of hematopoietic stem/progenitor and leukemia cells

Author: Aurore Hattabi, Ayda Miri-Nezhad, Isabelle Vigon, Aissa Benyoucef, Fabio Michelet, Evelyne Lauret, François Guillonneau, Serge Fichelson, Cécile Naudin, Françoise Pflumio, Isabelle Dusanter-Fourt, INSERM U1016, Institut Cochin, Paris, France, Université Paris Descartes, Sorbonne Paris Cité, Paris, France, Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 8104, Paris, France, Commissariat à l'Energie Atomique et aux Energies Alternatives, DSV-IRCM-SCSR-LSHL, UMR 967, Fontenay-aux-Roses, France, Inserm U967, Fontenay‐aux‐Roses cedex, France, Stabilité génétique, Cellules Souches et Radiations (SCSR (U_967)), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université Paris-Sud, UMR 967, Fontenay-aux-Roses, France, Plateforme protéomique 3P5 [Institut Cochin] (3P5), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Hematopoïèse et Cellules Souches (U362), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellules Souches et Radiations (SCSR (U967 / UMR-E_008)), Université Paris-Sud - Paris 11 (UP11)-Université Paris Diderot - Paris 7 (UPD7)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Cyclin-Dependent Kinase Inhibitor p21, Hematopoiesis and Stem Cells, [SDV]Life Sciences [q-bio], Immunology, RNA-binding protein, [SDV.CAN]Life Sciences [q-bio]/Cancer, Mice, SCID, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biology, Biochemistry, Small hairpin RNA, 03 medical and health sciences, Mice, 0302 clinical medicine, Mice, Inbred NOD, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Progenitor cell, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, Mice, Knockout, Cell growth, Myeloid leukemia, RNA-Binding Proteins, Forkhead Transcription Factors, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Cell Biology, Hematology, Hematopoietic Stem Cells, Cell biology, Neoplasm Proteins, Repressor Proteins, Haematopoiesis, 030104 developmental biology, Leukemia, Myeloid, 030220 oncology & carcinogenesis, Cancer research, Neoplastic Stem Cells, Stem cell, Cyclin-Dependent Kinase Inhibitor p27, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Adult stem cell, Signal Transduction
Abstract: International audience; Key Points • The RNA regulators PUMILIO sustain HSPC and acute myeloid leukemia cell growth by upregulating FOXP1 expression through direct binding to 2 FOXP1-39UTR PUMILIO-binding elements. • FOXP1 mediates PUMILIO growth-promoting activities by repressing expression of p21 CIP1 and p27 KIP1 cell cycle inhibitors. RNA-binding proteins (RBPs) have emerged as important regulators of invertebrate adult stem cells, but their activities remain poorly appreciated in mammals. Using a short hairpin RNA strategy, we demonstrate here that the 2 mammalian RBPs, PUMILIO (PUM)1 and PUM2, members of the PUF family of posttranscriptional regulators, are essential for hematopoietic stem/progenitor cell (HSPC) proliferation and survival in vitro and in vivo upon reconstitution assays. Moreover, we found that PUM1/2 sustain myeloid leukemic cell growth. Through a proteomic approach, we identified the FOXP1 transcription factor as a new target of PUM1/2. Contrary to its canonical repressive activity, PUM1/2 rather promote FOXP1 expression by a direct binding to 2 canonical PUM responsive elements present in the FOXP1-39 untranslated region (UTR). Expression of FOXP1 strongly correlates with PUM1 and PUM2 levels in primary HSPCs and myeloid leukemia cells. We demonstrate that FOXP1 by itself supports HSPC and leukemic cell growth, thus mimicking PUM activities. Mechanis-tically, FOXP1 represses the expression of the p21 2CIP1 and p27 2KIP1 cell cycle inhibitors. Enforced FOXP1 expression reverses shPUM antiproliferative and proapoptotic activities. Altogether, our results reveal a novel regulatory pathway, underscoring a previously unknown and interconnected key role of PUM1/2 and FOXP1 in regulating normal HSPC and leukemic cell growth.
Published: 2017
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43. SPRED1, a RAS MAPK pathway inhibitor that causes Legius syndrome, is a tumour suppressor downregulated in paediatric acute myeloblastic leukaemia

Author: Paola Ballerini, Armelle Luscan, Hélène Lapillonne, P Goussard, Dominique Vidaud, Eric Pasmant, Arnaud Petit, F Porteu, Pierre Vabres, I Naguibvena, Judith Landman-Parker, B de Laval, Caroline Deswarte, Brigitte Gilbert-Dussardier, F Brizard, Sylvie Fasola, Benjamin Uzan, Aurélia Gruber, Ingrid Laurendeau, Frédéric Millot, and Françoise Pflumio
Subjects: Male, Cancer Research, Adolescent, Loss of Heterozygosity, Frameshift mutation, Gene product, Loss of heterozygosity, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, hemic and lymphatic diseases, Genetics, medicine, Humans, Genes, Tumor Suppressor, Neurofibromatosis, Child, Molecular Biology, Adaptor Proteins, Signal Transducing, Legius syndrome, Neurofibromin 1, biology, Cafe-au-Lait Spots, Infant, Newborn, Intracellular Signaling Peptides and Proteins, Macrocephaly, Infant, Membrane Proteins, medicine.disease, Gene Expression Regulation, Neoplastic, Leukemia, Myeloid, Acute, Haematopoiesis, Genes, ras, Child, Preschool, Mutation, Cancer research, biology.protein, Female, medicine.symptom
Abstract: Constitutional dominant loss-of-function mutations in the SPRED1 gene cause a rare phenotype referred as neurofibromatosis type 1 (NF1)-like syndrome or Legius syndrome, consisted of multiple café-au-lait macules, axillary freckling, learning disabilities and macrocephaly. SPRED1 is a negative regulator of the RAS MAPK pathway and can interact with neurofibromin, the NF1 gene product. Individuals with NF1 have a higher risk of haematological malignancies. SPRED1 is highly expressed in haematopoietic cells and negatively regulates haematopoiesis. SPRED1 seemed to be a good candidate for leukaemia predisposition or transformation. We performed SPRED1 mutation screening and expression status in 230 paediatric lymphoblastic and acute myeloblastic leukaemias (AMLs). We found a loss-of-function frameshift SPRED1 mutation in a patient with Legius syndrome. In this patient, the leukaemia blasts karyotype showed a SPRED1 loss of heterozygosity, confirming SPRED1 as a tumour suppressor. Our observation confirmed that acute leukaemias are rare complications of the Legius syndrome. Moreover, SPRED1 was significantly decreased at RNA and protein levels in the majority of AMLs at diagnosis compared with normal or paired complete remission bone marrows. SPRED1 decreased expression correlated with genetic features of AML. Our study reveals a new mechanism which contributes to deregulate RAS MAPK pathway in the vast majority of paediatric AMLs.
Published: 2014
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44. Phenothiazines induce PP2A-mediated apoptosis in T cell acute lymphoblastic leukemia

Author: Alex Kentsis, A. Thomas Look, James E. Bradner, Frederic Baleydier, Ruta Grebliunaite, Jon C. Aster, Huipin Yuan, Andrew P. Weng, Françoise Pflumio, Li Pan, Lynn VerPlank, Jason J. Marineau, Stephanie Norton, Richard W.J. Groen, Frank An, Jason Burbank, Benjamin Uzan, Constantine S. Mitsiades, Hanno Steen, Sandrine Poglio, Nicola Tolliday, Casie Reed, Elena Kozakewich, Paul A. Clemons, Alejandro Gutierrez, and CCA - Innovative therapy
Subjects: Proteomics, Perphenazine, Time Factors, Cell Survival, T cell, Apoptosis, Pharmacology, Biology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Chromatography, Affinity, Mass Spectrometry, Animals, Genetically Modified, Dephosphorylation, Mice, Phenothiazines, In vivo, Cell Line, Tumor, medicine, Animals, Humans, Protein Phosphatase 2, Phosphorylation, Zebrafish, Dose-Response Relationship, Drug, Receptors, Notch, Pigmentation, Cell growth, General Medicine, Protein phosphatase 2, Disease Models, Animal, medicine.anatomical_structure, Cell culture, Dopamine Antagonists, Drug Screening Assays, Antitumor, Research Article, medicine.drug
Abstract: T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer that is frequently associated with activating mutations in NOTCH1 and dysregulation of MYC. Here, we performed 2 complementary screens to identify FDA-approved drugs and drug-like small molecules with activity against T-ALL. We developed a zebrafish system to screen small molecules for toxic activity toward MYC-overexpressing thymocytes and used a human T-ALL cell line to screen for small molecules that synergize with Notch inhibitors. We identified the antipsychotic drug perphenazine in both screens due to its ability to induce apoptosis in fish, mouse, and human T-ALL cells. Using ligand-affinity chromatography coupled with mass spectrometry, we identified protein phosphatase 2A (PP2A) as a perphenazine target. T-ALL cell lines treated with perphenazine exhibited rapid dephosphorylation of multiple PP2A substrates and subsequent apoptosis. Moreover, shRNA knockdown of specific PP2A subunits attenuated perphenazine activity, indicating that PP2A mediates the drug's antileukemic activity. Finally, human T-ALLs treated with perphenazine exhibited suppressed cell growth and dephosphorylation of PP2A targets in vitro and in vivo. Our findings provide a mechanistic explanation for the recurring identification of phenothiazines as a class of drugs with anticancer effects. Furthermore, these data suggest that pharmacologic PP2A activation in T-ALL and other cancers driven by hyperphosphorylated PP2A substrates has therapeutic potential.
Published: 2014
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45. Triggering the TCR Developmental Checkpoint Activates a Therapeutically Targetable Tumor Suppressive Pathway in T-cell Leukemia

Author: David-Alexandre Gross, Melania Tesio, Amélie Trinquand, Mohamed Belhocine, Hervé Dombret, Norbert Ifrah, Benedetta Zaniboni, Lucienne Chatenoud, Vahid Asnafi, Francesca Rocchetti, François-Loïc Cosset, Nuno R. dos Santos, Christine Tran Quang, Ludovic Lhermitte, Jacques Ghysdael, Elizabeth Macintyre, Michael Dussiot, Françoise Pflumio, Olivier Hermine, Els Verhoeyen, Cindy Da Costa de Jesus, Salvatore Spicuglia, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Algarve [Portugal], Stress génotoxiques et cancer, Université Paris-Sud - Paris 11 (UP11)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Technologies avancées pour le génôme et la clinique (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Equipe 'Contrôle Métabolique des Morts Cellulaires' (INSERM U1065 - C3M), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Laboratoire de Recherche sur les Cellules Souches Hématopoiétiques et Leucémiques (LSHL), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Tolérance immunitaire et présentation antigénique: impact en auto-immunité et en transplantation, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Necker Enfants-Malades (INEM) ( INEM - UM 111 (UMR 8253 / U1151) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Technologies avancées pour le génôme et la clinique ( TAGC ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratory of Excellence GR-Ex, Sorbonne Paris Cité-Université Paris Descartes - Paris 5 ( UPD5 ) -Imagine Institute, Centre International de Recherche en Infectiologie ( CIRI ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Boehringer Ingelheim RCV, Service de Chimie Moléculaire ( SCM ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ), Hematology Department, Université d'Angers ( UA ), Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers, Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Service d'hématologie-immunologie-oncologie pédiatrique, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université Paris-Sud - Paris 11 (UP11)-Institut Curie-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (Equipe EVIR), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Centre hospitalier universitaire de Nantes (CHU Nantes)-Faculté de Médecine d'Angers-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Laennec-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôtel-Dieu de Nantes, Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Paris-Sud - Paris 11 (UP11), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Leukemia, T-Cell, CD3 Complex, medicine.medical_treatment, CD3, T-Lymphocytes, [SDV]Life Sciences [q-bio], T-cell leukemia, Receptors, Antigen, T-Cell, Antigen-Presenting Cells, Apoptosis, Biology, Lymphocyte Activation, Targeted therapy, Immunophenotyping, 03 medical and health sciences, Mice, medicine, Animals, Humans, Clonal Selection, Antigen-Mediated, Mice, Knockout, [ SDV ] Life Sciences [q-bio], T-cell receptor, Antibodies, Monoclonal, medicine.disease, 3. Good health, Leukemia, Disease Models, Animal, 030104 developmental biology, Oncology, Tumor progression, Immunology, Cancer cell, biology.protein, Female, Signal Transduction
Abstract: Cancer onset and progression involves the accumulation of multiple oncogenic hits, which are thought to dominate or bypass the physiologic regulatory mechanisms in tissue development and homeostasis. We demonstrate in T-cell acute lymphoblastic leukemia (T-ALL) that, irrespective of the complex oncogenic abnormalities underlying tumor progression, experimentally induced, persistent T-cell receptor (TCR) signaling has antileukemic properties and enforces a molecular program resembling thymic negative selection, a major developmental event in normal T-cell development. Using mouse models of T-ALL, we show that induction of TCR signaling by high-affinity self-peptide/MHC or treatment with monoclonal antibodies to the CD3ϵ chain (anti-CD3) causes massive leukemic cell death. Importantly, anti-CD3 treatment hampered leukemogenesis in mice transplanted with either mouse- or patient-derived T-ALLs. These data provide a strong rationale for targeted therapy based on anti-CD3 treatment of patients with TCR-expressing T-ALL and demonstrate that endogenous developmental checkpoint pathways are amenable to therapeutic intervention in cancer cells. Significance: T-ALLs are aggressive malignant lymphoid proliferations of T-cell precursors characterized by high relapse rates and poor prognosis, calling for the search for novel therapeutic options. Here, we report that the lineage-specific TCR/CD3 developmental checkpoint controlling cell death in normal T-cell progenitors remains switchable to induce massive tumor cell apoptosis in T-ALL and is amenable to preclinical therapeutic intervention. Cancer Discov; 6(9); 972–85. ©2016 AACR. See related commentary by Lemonnier and Mak, p. 946. This article is highlighted in the In This Issue feature, p. 932
Published: 2016
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46. DNMT3AR882H mutant and Tet2 inactivation cooperate in the deregulation of DNA methylation control to induce lymphoid malignancies in mice

Author: Cécile K. Lopez, Kristian Helin, Elena Mylonas, Michaela Fontenay, Enguerran Mouly, Françoise Pflumio, P. Gaulard, Marianne Terndrup Pedersen, M'Boyba Diop, Michael Weber, Laurianne Scourzic, Lucile Couronné, Nathalie Droin, O. Bernard, Julien Calvo, Patrice Dubreuil, Ambre Bender, Philippe Dessen, N Martin, V Della Valle, Sylvain Guibert, Thomas Mercher, Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), Hématopoïèse normale et pathologique ( U1170 Inserm ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Gustave Roussy ( IGR ), Génétique des tumeurs ( U985 ), Institut Gustave Roussy ( IGR ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Norwegian Defence Intelligence School [Oslo] ( NDUC ), Centre de recherche en économie et management ( CREM ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ), Centro de Aplicaciones de Tecnologías de Avanzada ( CENATAV ), CENATAV, Laboratoire Ligérien de Linguistique ( LLL ), Bibliothèque nationale de France ( BnF ) -Université d'Orléans ( UO ) -Université de Tours-Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), The Unilever Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge [UK] ( CAM ), Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Images et Modèles, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé ( CREATIS ), Université Jean Monnet [Saint-Étienne] ( UJM ) -Hospices Civils de Lyon ( HCL ) -Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Jean Monnet [Saint-Étienne] ( UJM ) -Hospices Civils de Lyon ( HCL ) -Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), and Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: 0301 basic medicine, Cancer Research, Myeloid, Cellular differentiation, Notch signaling pathway, Biology, Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire, medicine.disease_cause, Article, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, DNA Methyltransferase 3A, Dioxygenases, 03 medical and health sciences, Mice, Proto-Oncogene Proteins, medicine, Animals, Genes, Tumor Suppressor, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, DNA (Cytosine-5-)-Methyltransferases, Mutation, Receptors, Notch, Myeloid leukemia, Cell Differentiation, Hematology, DNA Methylation, Lymphoproliferative Disorders, Transplantation, Gene expression profiling, DNA-Binding Proteins, 030104 developmental biology, medicine.anatomical_structure, Oncology, embryonic structures, DNA methylation, Immunology, Cancer research
Abstract: International audience; TEN-ELEVEN-TRANSLOCATION-2 (TET2) and DNA-METHYLTRANSFERASE-3A (DNMT3A), both encoding proteins involved in regulating DNA methylation, are mutated in hematological malignancies affecting both myeloid and lymphoid lineages. We previously reported an association of TET2 and DNMT3A mutations in progenitors of patients with angioimmunoblastic T-cell lymphomas (AITL). Here, we report on the cooperative effect of Tet2 inactivation and DNMT3A mutation affecting arginine 882 (DNMT3A(R882H)) using a murine bone marrow transplantation assay. Five out of eighteen primary recipients developed hematological malignancies with one mouse developing an AITL-like disease, two mice presenting acute myeloid leukemia (AML)-like and two others T-cell acute lymphoblastic leukemia (T-ALL)-like diseases within 6 months following transplantation. Serial transplantations of DNMT3A(R882H) Tet2(-/-) progenitors led to a differentiation bias toward the T-cell compartment, eventually leading to AITL-like disease in 9/12 serially transplanted recipients. Expression profiling suggested that DNMT3A(R882H) Tet2(-/-) T-ALLs resemble those of NOTCH1 mutant. Methylation analysis of DNMT3A(R882H) Tet2(-/-) T-ALLs showed a global increase in DNA methylation affecting tumor suppressor genes and local hypomethylation affecting genes involved in the Notch pathway. Our data confirm the transformation potential of DNMT3A(R882H) Tet2(-/-) progenitors and represent the first cooperative model in mice involving Tet2 inactivation driving lymphoid malignancies.
Published: 2016
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47. Architectural and functional heterogeneity of hematopoietic stem/progenitor cells in non-del(5q) myelodysplastic syndromes

Author: M'Boyba Diop, Carine Lefevre, Sophie Raynaud, Nicolas Chapuis, Marie-Laure Arcangeli, Meyling Cheok, Lise Willems, Laurence Legros, Evelyne Lauret, Caroline Delette, Virginie Chesnais, Didier Bouscary, Sabrina Bondu, Alice Rousseau, Hélène Guermouche, Olivier A. Bernard, Michaela Fontenay, Françoise Pflumio, and Olivier Kosmider
Subjects: 0301 basic medicine, Myeloid, Clone (cell biology), Gene Expression, Antigens, CD34, Cell Cycle Proteins, Gene mutation, Biochemistry, Mice, 0302 clinical medicine, Mice, Inbred NOD, hemic and lymphatic diseases, Myeloid Cells, Lymphocytes, Genetics, Membrane Glycoproteins, Hematopoietic stem cell, Myeloid leukemia, Antigens, Nuclear, Cell Differentiation, Hematology, Haematopoiesis, Leukemia, Myeloid, Acute, medicine.anatomical_structure, Phenotype, 030220 oncology & carcinogenesis, Gene Knockdown Techniques, Disease Progression, Chromosomes, Human, Pair 5, Female, Lineage (genetic), Immunology, Transplantation, Heterologous, Biology, Immunophenotyping, 03 medical and health sciences, Proto-Oncogene Proteins, medicine, Animals, Humans, Cell Lineage, Progenitor cell, Cell Biology, Hematopoietic Stem Cells, ADP-ribosyl Cyclase 1, Clone Cells, Repressor Proteins, 030104 developmental biology, Myelodysplastic Syndromes, Mutation, Cancer research
Abstract: Myelodysplastic syndromes (MDSs) are hematopoietic stem cell disorders in which recurrent mutations define clonal hematopoiesis. The origin of the phenotypic diversity of non-del(5q) MDS remains unclear. Here, we investigated the clonal architecture of the CD34+CD38- hematopoietic stem/progenitor cell (HSPC) compartment and interrogated dominant clones for MDS-initiating cells. We found that clones mainly accumulate mutations in a linear succession with retention of a dominant subclone. The clone detected in the long-term culture-initiating cell compartment that reconstitutes short-term human hematopoiesis in xenotransplantation models is usually the dominant clone, which gives rise to the myeloid and to a lesser extent to the lymphoid lineage. The pattern of mutations may differ between common myeloid progenitors (CMPs), granulomonocytic progenitors (GMPs), and megakaryocytic-erythroid progenitors (MEPs). Rare STAG2 mutations can amplify at the level of GMPs, from which it may drive the transformation to acute myeloid leukemia. We report that major truncating BCOR gene mutation affecting HSPC and CMP was beneath the threshold of detection in GMP or MEP. Consistently, BCOR knock-down (KD) in normal CD34+ progenitors modifies their granulocytic and erythroid differentiation. Clonal architecture of the HSPC compartment and mutations selected during differentiation contribute to the phenotypic heterogeneity of MDS. Defining the hierarchy of driver mutations provides insights into the process of transformation and may guide the search for novel therapeutic strategies.
Published: 2016

48. L’ETO se resserre sur les leucémies aiguës mégacaryoblastiques

Author: John D. Crispino, Paola Ballerini, Françoise Pflumio, Olivier Bernard, Thomas Mercher, and Clarisse Thiollier
Subjects: Acute megakaryoblastic leukemia, Leukemia, GLIS2, Oncogene Proteins, medicine, Cancer research, General Medicine, Biology, medicine.disease, General Biochemistry, Genetics and Molecular Biology, Therapeutic strategy, Chromosomal inversion
Published: 2012
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49. Human Adipose-Derived Stromal Cells Efficiently Support Hematopoiesis In Vitro and In Vivo: A Key Step for Therapeutic Studies

Author: Philippe Bourin, Françoise Pflumio, Béatrice Cousin, Fabienne De Toni, Patrick Laharrague, Louis Casteilla, Sandrine Poglio, and Aissa Ben Youcef
Subjects: Adult, Male, Stromal cell, Adipose tissue, Antigens, CD34, Biology, Mesenchymal Stem Cell Transplantation, Subcutaneous fat, Mice, In vivo, medicine, Animals, Humans, Cell Lineage, Aged, Cell Proliferation, Aged, 80 and over, Mesenchymal stem cell, Cell Differentiation, Mesenchymal Stem Cells, Cell Biology, Hematology, Middle Aged, Hematopoietic Stem Cells, In vitro, Hematopoiesis, Haematopoiesis, medicine.anatomical_structure, Adipose Tissue, Immunology, Cancer research, Female, Bone marrow, Developmental Biology
Abstract: Adipose-derived stromal cells (ADSCs) are close relatives of bone marrow mesenchymal stromal cells (BM-MSCs). The ease of access to subcutaneous fat pad and the abundance of stromal precursors make fat tissue an attractive source of stromal cells for clinicians. However, their ability to support hematopoietic stem cells in vitro and in vivo has not been established definitively. Thus, their usefulness in supporting hematopoietic stem cell engraftment is not as clear as with BM-MSCs. In this article, we show that human ADSCs, cultured with a good manufacturing practice medium, maintain in vitro human early and committed hematopoietic progenitors and support their complete differentiation toward myeloid and lymphoid lineages. Compared with BM-MSCs, ADSCs elicit a more precocious early progenitor formation and faster proliferation and differentiation of hematopoietic progenitors. Further, in vivo, when co-injected in NOD.Cg-Prkdc(scid) Il2(rgtm1Wjl)/SzJ (NSG) mice with a low number of human CD34(+) cells, ADSCs enabled the higher production of immature human hematopoietic progenitors and CD45(+) cells when compared with BM-MSCs. As a whole, our results indicate that human ADSCs, isolated and expanded under clinical-grade conditions, support hematopoiesis in vitro and in vivo and thus provide the rationale for their use in supporting hematopoietic reconstitution in clinical settings.
Published: 2011
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50. Alternative Lengthening of Telomeres in Human Glioma Stem Cells

Author: Marc-André Mouthon, Françoise Pflumio, David C. Silvestre, Jose R. Pineda, François D. Boussin, Marie-Pierre Junier, Françoise Hoffschir, Hervé Chneiweiss, and J. M. Studler
Subjects: Adult, Male, Telomerase, Transplantation, Heterologous, Stem cell theory of aging, Mice, Transgenic, Mice, SCID, Biology, Mice, Mice, Inbred NOD, Cancer stem cell, Radioresistance, Tumor Cells, Cultured, Animals, Humans, Telomerase reverse transcriptase, In Situ Hybridization, Fluorescence, Aged, Brain Neoplasms, Glioma, Cell Biology, Middle Aged, Telomere, Molecular biology, Neural stem cell, Neoplastic Stem Cells, Cancer research, Molecular Medicine, Female, Stem cell, Developmental Biology
Abstract: Cancer stem cells are increasingly recognized as major therapeutic targets. We report here the isolation of glioma stem cells (GSCs) maintaining telomere length through a telomerase-independent mechanism known as alternative lengthening of telomeres (ALTs). TG20 cells were isolated from a glioblastoma multiforme, which had the ALT phenotype. They have no detectable telomerase activity and extremely long and heterogeneous telomeres colocalizing with promyelocytic leukemia bodies. The cancer stem cell potential of TG20 cells was confirmed based on their expression of neural stem cell markers, their capacity of in vitro long-term proliferation and to form intracranial tumors in immune-deficient mice. Interestingly, we found that both in vitro and in vivo TG20 cells were significantly more resistant to ionizing radiation than GSCs with telomerase activity. Analysis of DNA damage foci, DNA double-strand breaks repair, and chromosome instability suggest that radiation resistance was related to interference of ALT pathway with DNA damage response. Therefore, our data show for the first time that the ALT pathway can confer to cancer stem cells the capacity to sustain long-term proliferation as telomerase activity and importantly may also affect treatment efficiency. TG20 cells are thus the first cellular model of GSCs displaying ALT and should prove to be useful for the development of specific treatment strategies.
Published: 2011
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