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1. Low-dose non-steroidal anti-inflammatory drugs: a promising approach for the treatment of symptomatic bone marrow failure in Ghosal hematodiaphyseal dysplasia

Author

Jonathan Bordat, Felipe Suarez, Valérie Cormier-Daire, Regis Peffault de Latour, Jean Soulier, Veronique Meignin, Mathilde Doyard, Lise Larcher, Stephane Vanderbecken, and Flore Sicre de Fontbrune

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Not available.

Published
2024
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3. P315: TP53 ALTERATIONS AND MRD REFINE PROGNOSIS OF ADULT KMT2A-REARRANGED B-ALL

Author

Rathana Kim, Hugo Bergugnat, Florence Pasquier, Emmanuel Raffoux, Lise Larcher, Marie Passet, Cedric Pastoret, Grardel Nathalie, Vahid Asnafi, Eric Delabesse, Aurélie Caye-Eude, Claus Meyer, Rolf Masrschalek, Anne Thiebaut-Bertrand, Marie Balsat, Martine Escoffre, Sabine Blum, Michael Baumann, Anne Banos, Nicole Straetmans, Maria Pilar Gallego Hernanz, Yves Chalandon, Carlos Graux, Thibaut Leguay, Mathilde Hunault, Françoise Huguet, Véronique Lhéritier, Jean Soulier, Nicolas Boissel, and Emmanuelle Clappier

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2023
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4. Allogeneic transplantation in acute myelogenous leukemia: a comprehensive single institution's experience

Author

Gerard Socie, Jacques-Emmanuel Galimard, Emmanuel Raffoux, Raphael Itzykson, Pierre Edouard Debureaux, David Michonneau, Etienne Lengliné, Marie Robin, Flore Sicre de Fontbrune, Marie Sébert, Aliénor Xhaard, Rathana Kim, Anne Couprie, Nathalie Dhedin, Matteo Dragani, Pierre Lemaire, Lise Larcher, Emmanuelle Clappier, Nicolas Boissel, Jean Soulier, Hervé Dombret, Pierre Fenaux, Régis Peffault de Latour, and Lionel Adès

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Debates on the role and timing of allogeneic hemtopoietic stem cell transplantation (HSCT) in acute myelogenous leukemia (AML) have persisted for decades. Time to transplant introduces an immortal time and current treatment algorithm mainly relies on the European LeukemiaNet disease risk classification. Previous studies are also limited to age groups, remission status and other ill-defined parameters. We studied all patients at diagnosis irrespective of age and comorbidities to estimate the cumulative incidence and potential benefit or disadvantage of HSCT in a single center. As a time-dependent covariate, HSCT improved overall survival in intermediate- and poor-risk patients (hazard ratio =0.51; P=0.004). In goodrisk patients only eight were transplanted in first complete remission. Overall, the 4-year cumulative incidence of HSCT was only 21.9% but was higher (52.1%) for patients in the first age quartile (16-57 years old) and 26.4% in older patients (57-70 years old) (P

Published
2023
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5. Improved collection of hematopoietic stem cells and progenitors from Fanconi anemia patients for gene therapy purposes

Author

Julián Sevilla, Susana Navarro, Paula Rio, Rebeca Sánchez-Domínguez, Josune Zubicaray, Eva Gálvez, Eva Merino, Elena Sebastián, Carmen Azqueta, José A. Casado, José C. Segovia, Omaira Alberquilla, Massimo Bogliolo, Francisco J. Román-Rodríguez, Yari Giménez, Lise Larcher, Rocío Salgado, Roser M. Pujol, Raquel Hladun, Ana Castillo, Jean Soulier, Sergi Querol, Jesús Fernández, Jonathan Schwartz, Nagore García de Andoín, Ricardo López, Albert Catalá, Jordi Surralles, Cristina Díaz-de-Heredia, and Juan A. Bueren

Subjects
Fanconi anemia, HSPC collection, gene therapy, Mozobil, mobilization, leukapheresis, Genetics, QH426-470, Cytology, QH573-671
Abstract

Difficulties in the collection of hematopoietic stem and progenitor cells (HSPCs) from Fanconi anemia (FA) patients have limited the gene therapy in this disease. We have investigated (ClinicalTrials.gov, NCT02931071) the safety and efficacy of filgrastim and plerixafor for mobilization of HSPCs and collection by leukapheresis in FA patients. Nine of eleven enrolled patients mobilized beyond the threshold level of 5 CD34+ cells/μL required to initiate apheresis. A median of 21.8 CD34+ cells/μL was reached at the peak of mobilization. Significantly, the oldest patients (15 and 16 years old) were the only ones who did not reach that threshold. A median of 4.27 million CD34+ cells/kg was collected in 2 or 3 aphereses. These numbers were markedly decreased to 1.1 million CD34+ cells/kg after immunoselection, probably because of weak expression of the CD34 antigen. However, these numbers were sufficient to facilitate the engraftment of corrected HSPCs in non-conditioned patients. No procedure-associated serious adverse events were observed. Mobilization of CD34+ cells correlated with younger age, higher leukocyte counts and hemoglobin values, lower mean corpuscular volume, and higher proportion of CD34+ cells in bone marrow (BM). All these values offer crucial information for the enrollment of FA patients for gene therapy protocols.

Published
2021
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6. XPC deficiency increases risk of hematologic malignancies through mutator phenotype and characteristic mutational signature

Author

Andrey A. Yurchenko, Ismael Padioleau, Bakhyt T. Matkarimov, Jean Soulier, Alain Sarasin, and Sergey Nikolaev

Subjects
Science
Abstract

Xeroderma Pigmentosum group C (XP-C) is a rare genetic disorder characterised by deficient DNA repair leading to skin and internal cancer, but the latter is not well understood molecularly. Here the authors sequence genomes of non-skin cancers from XP-C patients to unravel its mutational patterns.

Published
2020
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7. ClinGen Myeloid Malignancy Variant Curation Expert Panel recommendations for germline RUNX1 variants

Author

Xi Luo, Simone Feurstein, Shruthi Mohan, Christopher C. Porter, Sarah A. Jackson, Sioban Keel, Michael Chicka, Anna L. Brown, Chimene Kesserwan, Anupriya Agarwal, Minjie Luo, Zejuan Li, Justyne E. Ross, Panagiotis Baliakas, Daniel Pineda-Alvarez, Courtney D. DiNardo, Alison A. Bertuch, Nikita Mehta, Tom Vulliamy, Ying Wang, Kim E. Nichols, Luca Malcovati, Michael F. Walsh, Lesley H. Rawlings, Shannon K. McWeeney, Jean Soulier, Anna Raimbault, Mark J. Routbort, Liying Zhang, Gabriella Ryan, Nancy A. Speck, Sharon E. Plon, David Wu, and Lucy A. Godley

Subjects
Specialties of internal medicine, RC581-951
Abstract

Abstract: Standardized variant curation is essential for clinical care recommendations for patients with inherited disorders. Clinical Genome Resource (ClinGen) variant curation expert panels are developing disease-associated gene specifications using the 2015 American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines to reduce curation discrepancies. The ClinGen Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP) was created collaboratively between the American Society of Hematology and ClinGen to perform gene- and disease-specific modifications for inherited myeloid malignancies. The MM-VCEP began optimizing ACMG/AMP rules for RUNX1 because many germline variants have been described in patients with familial platelet disorder with a predisposition to acute myeloid leukemia, characterized by thrombocytopenia, platelet functional/ultrastructural defects, and a predisposition to hematologic malignancies. The 28 ACMG/AMP codes were tailored for RUNX1 variants by modifying gene/disease specifications, incorporating strength adjustments of existing rules, or both. Key specifications included calculation of minor allele frequency thresholds, formulating a semi-quantitative approach to counting multiple independent variant occurrences, identifying functional domains and mutational hotspots, establishing functional assay thresholds, and characterizing phenotype-specific guidelines. Preliminary rules were tested by using a pilot set of 52 variants; among these, 50 were previously classified as benign/likely benign, pathogenic/likely pathogenic, variant of unknown significance (VUS), or conflicting interpretations (CONF) in ClinVar. The application of RUNX1-specific criteria resulted in a reduction in CONF and VUS variants by 33%, emphasizing the benefit of gene-specific criteria and sharing internal laboratory data.

Published
2019
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8. Studies in an Early Development Window Unveils a Severe HSC Defect in both Murine and Human Fanconi Anemia

Author

Carine Domenech, Loïc Maillard, Alix Rousseau, Fabien Guidez, Laurence Petit, Marika Pla, Denis Clay, Fabien Guimiot, Sandra Sanfilippo, Sebastien Jacques, Pierre de la Grange, Noémie Robil, Jean Soulier, and Michèle Souyri

Subjects
Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract

Summary: Fanconi anemia (FA) causes bone marrow failure early during childhood, and recent studies indicate that a hematopoietic defect could begin in utero. We performed a unique kinetics study of hematopoiesis in Fancg−/− mouse embryos, between the early embryonic day 11.5 (E11.5) to E12.5 developmental window (when the highest level of hematopoietic stem cells [HSC] amplification takes place) and E14.5. This study reveals a deep HSC defect with exhaustion of proliferative and self-renewal capacities very early during development, together with severe FA clinical and biological manifestations, which are mitigated at E14.5 due to compensatory mechanisms that help to ensure survival of Fancg−/− embryos. It also reports that a deep HSC defect is also observed during human FA development, and that human FA fetal liver (FL) HSCs present a transcriptome profile similar to that of mouse E12.5 Fancg−/− FL HSCs. Altogether, our results highlight that early mouse FL could represent a good alternative model for studying Fanconi pathology. : A deep HSC defect is present very early during Fancg−/− mouse embryonic development, and is also reported for the first time during human Fanconi anemia development. At E14.5, functional and molecular compensation in Fancg−/− FL HSCs help ensure the survival of Fancg−/− embryos. Altogether E12.5 Fancg−/− FL could represent a good model for studying Fanconi pathology. Keywords: HSC, Fanconi anemia, mouse embryonic development, human embryonic development, placenta, fetal liver, transcriptome

Published
2018
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9. Detectable clonal mosaicism in blood as a biomarker of cancer risk in Fanconi anemia

Author

Judith Reina-Castillón, Roser Pujol, Marcos López-Sánchez, Benjamín Rodríguez-Santiago, Miriam Aza-Carmona, Juan Ramón González, José Antonio Casado, Juan Antonio Bueren, Julián Sevilla, Isabel Badel, Albert Català, Cristina Beléndez, María Ángeles Dasí, Cristina Díaz de Heredia, Jean Soulier, Detlev Schindler, Luis Alberto Pérez-Jurado, and Jordi Surrallés

Subjects
Specialties of internal medicine, RC581-951
Abstract

Abstract: Detectable clonal mosaicism for large chromosomal events has been associated with aging and an increased risk of hematological and some solid cancers. We hypothesized that genetic cancer predisposition disorders, such as Fanconi anemia (FA), could manifest a high rate of chromosomal mosaic events (CMEs) in peripheral blood, which could be used as early biomarkers of cancer risk. We studied the prevalence of CMEs by single-nucleotide polymorphism (SNP) array in 130 FA patients' blood DNA and their impact on cancer risk. We detected 51 CMEs (4.4-159 Mb in size) in 16 out of 130 patients (12.3%), of which 9 had multiple CMEs. The most frequent events were gains at 3q (n = 6) and 1q (n = 5), both previously associated with leukemia, as well as rearrangements with breakpoint clustering within the major histocompatibility complex locus (P = 7.3 × 10−9). Compared with 15 743 age-matched population controls, FA patients had a 126 to 140 times higher risk of detectable CMEs in blood (P < 2.2 × 10−16). Prevalent and incident hematologic and solid cancers were more common in CME carriers (odds ratio [OR] = 11.6, 95% confidence interval [CI] = 3.4-39.3, P = 2.8 × 10−5), leading to poorer prognosis. The age-adjusted hazard risk (HR) of having cancer was almost 5 times higher in FA individuals with CMEs than in those without CMEs. Regarding survival, the HR of dying was 4 times higher in FA individuals having CMEs (HR = 4.0, 95% CI = 2.0-7.9, P = 5.7 × 10−5). Therefore, our data suggest that molecular karyotyping with SNP arrays in easy-to-obtain blood samples could be used for better monitoring of bone marrow clonal events, cancer risk, and overall survival of FA patients.

Published
2017
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10. Extended clinical and genetic spectrum associated with biallelic RTEL1 mutations

Author

Fabien Touzot, Laetitia Kermasson, Laurent Jullien, Despina Moshous, Christelle Ménard, Aydan Ikincioğullari, Figen Doğu, Sinan Sari, Vannina Giacobbi-Milet, Amos Etzioni, Jean Soulier, Arturo Londono-Vallejo, Alain Fischer, Isabelle Callebaut, Jean-Pierre de Villartay, Thierry Leblanc, Caroline Kannengiesser, and Patrick Revy

Subjects
Specialties of internal medicine, RC581-951
Abstract

Abstract: Telomeres are repetitive hexameric sequences located at the end of linear chromosomes. They adopt a lariat-like structure, the T-loop, to prevent them from being recognized as DNA breaks by the DNA repair machinery. RTEL1 is a DNA helicase required for proper telomere replication and stability. In particular, it has been postulated that RTEL1 is involved in the opening of the T-loop during telomere replication to avoid sudden telomere deletion and telomere circle (T-circle) formation. In humans, biallelic RTEL1 mutations cause Hoyeraal-Hreidarsson syndrome (HH), a rare and severe telomere biology disorder characterized by intrauterine growth retardation, bone marrow failure, microcephaly and/or cerebellar hypoplasia, and immunodeficiency. To date, 18 different RTEL1 mutations have been described in 19 cases of HH with short telomeres. The impaired T-loop resolution has been proposed to be a major cause of telomere shortening in RTEL1 deficiency. However, the biological and clinical consequences of this disorder remain incompletely documented. Here, we describe 4 new patients harboring biallelic RTEL1 mutations, including 2 novel missense mutations located in the C-terminal end of RTEL1 (p.Cys1268Arg and p.Val1294Phe). Clinical characteristics from these 4 patients were collected as those from 4 other RTEL1-deficient patients previously reported. In addition, we assessed whether T-circles, the product of improper T-loop resolution, were detected in our RTEL1-deficient patients. Overall, our study broadens and refines the clinical and biological spectrum of human RTEL1 deficiency.

Published
2016
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12. A comprehensive inventory of TLX1 controlled long non-coding RNAs in T-cell acute lymphoblastic leukemia through polyA+ and total RNA sequencing

Author

Karen Verboom, Wouter Van Loocke, Pieter-Jan Volders, Bieke Decaesteker, Francisco Avila Cobos, Simon Bornschein, Charles E. de Bock, Zeynep Kalender Atak, Emmanuelle Clappier, Stein Aerts, Jan Cools, Jean Soulier, Tom Taghon, Pieter Van Vlierberghe, Jo Vandesompele, Frank Speleman, and Kaat Durinck

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2018
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13. MB4-2 breakpoint in MMSET combined with del(17p) defines a subset of t(4;14) multiple myeloma with very poor prognosis

Author

Anne Lazareth, Xiu-Yi Song, Aurelie Coquin, Stephanie Harel, Lionel Karlin, Karim Belhadj, Damien Roos-Weil, Laurent Frenzel, Jerôme Tamburini, Margaret Macro, Sylvie Chevret, Hervé Avet Loiseau, Stephane Minvielle, Jean Paul Fermand, Jean Soulier, Jean Christophe Bories, and Bertrand Arnulf

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2015
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14. Targeted sequencing identifies associations between IL7R-JAK mutations and epigenetic modulators in T-cell acute lymphoblastic leukemia

Author

Carmen Vicente, Claire Schwab, Michaël Broux, Ellen Geerdens, Sandrine Degryse, Sofie Demeyer, Idoya Lahortiga, Alannah Elliott, Lucy Chilton, Roberta La Starza, Cristina Mecucci, Peter Vandenberghe, Nicholas Goulden, Ajay Vora, Anthony V. Moorman, Jean Soulier, Christine J. Harrison, Emmanuelle Clappier, and Jan Cools

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

T-cell acute lymphoblastic leukemia is caused by the accumulation of multiple oncogenic lesions, including chromosomal rearrangements and mutations. To determine the frequency and co-occurrence of mutations in T-cell acute lymphoblastic leukemia, we performed targeted re-sequencing of 115 genes across 155 diagnostic samples (44 adult and 111 childhood cases). NOTCH1 and CDKN2A/B were mutated/deleted in more than half of the cases, while an additional 37 genes were mutated/deleted in 4% to 20% of cases. We found that IL7R-JAK pathway genes were mutated in 27.7% of cases, with JAK3 mutations being the most frequent event in this group. Copy number variations were also detected, including deletions of CREBBP or CTCF and duplication of MYB. FLT3 mutations were rare, but a novel extracellular mutation in FLT3 was detected and confirmed to be transforming. Furthermore, we identified complex patterns of pairwise associations, including a significant association between mutations in IL7R-JAK genes and epigenetic regulators (WT1, PRC2, PHF6). Our analyses showed that IL7R-JAK genetic lesions did not confer adverse prognosis in T-cell acute lymphoblastic leukemia cases enrolled in the UK ALL2003 trial. Overall, these results identify interconnections between the T-cell acute lymphoblastic leukemia genome and disease biology, and suggest a potential clinical application for JAK inhibitors in a significant proportion of patients with T-cell acute lymphoblastic leukemia.

Published
2015
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15. The Notch driven long non-coding RNA repertoire in T-cell acute lymphoblastic leukemia

Author

Kaat Durinck, Annelynn Wallaert, Inge Van de Walle, Wouter Van Loocke, Pieter-Jan Volders, Suzanne Vanhauwaert, Ellen Geerdens, Yves Benoit, Nadine Van Roy, Bruce Poppe, Jean Soulier, Jan Cools, Pieter Mestdagh, Jo Vandesompele, Pieter Rondou, Pieter Van Vlierberghe, Tom Taghon, and Frank Speleman

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Genetic studies in T-cell acute lymphoblastic leukemia have uncovered a remarkable complexity of oncogenic and loss-of-function mutations. Amongst this plethora of genetic changes, NOTCH1 activating mutations stand out as the most frequently occurring genetic defect, identified in more than 50% of T-cell acute lymphoblastic leukemias, supporting a role as an essential driver for this gene in T-cell acute lymphoblastic leukemia oncogenesis. In this study, we aimed to establish a comprehensive compendium of the long non-coding RNA transcriptome under control of Notch signaling. For this purpose, we measured the transcriptional response of all protein coding genes and long non-coding RNAs upon pharmacological Notch inhibition in the human T-cell acute lymphoblastic leukemia cell line CUTLL1 using RNA-sequencing. Similar Notch dependent profiles were established for normal human CD34+ thymic T-cell progenitors exposed to Notch signaling activity in vivo. In addition, we generated long non-coding RNA expression profiles (array data) from ex vivo isolated Notch active CD34+ and Notch inactive CD4+CD8+ thymocytes and from a primary cohort of 15 T-cell acute lymphoblastic leukemia patients with known NOTCH1 mutation status. Integration of these expression datasets with publicly available Notch1 ChIP-sequencing data resulted in the identification of long non-coding RNAs directly regulated by Notch activity in normal and malignant T cells. Given the central role of Notch in T-cell acute lymphoblastic leukemia oncogenesis, these data pave the way for the development of novel therapeutic strategies that target hyperactive Notch signaling in human T-cell acute lymphoblastic leukemia.

Published
2014
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18. Breakpoint-specific multiplex polymerase chain reaction allows the detection of IKZF1 intragenic deletions and minimal residual disease monitoring in B-cell precursor acute lymphoblastic leukemia

Author

Aurélie Caye, Kheïra Beldjord, Kelly Mass-Malo, Séverine Drunat, Jean Soulier, Virginie Gandemer, André Baruchel, Yves Bertrand, Hélène Cavé, and Emmanuelle Clappier

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Deletion of the Ikaros (IKZF1) gene is an oncogenic lesion frequently associated with BCR-ABL1-positive acute lymphoblastic leukemias. It is also found in a fraction of BCR-ABL1-negative B-cell precursor acute lymphoblastic leukemias, and early studies showed it was associated with a higher risk of relapse. Therefore, screening tools are needed for evaluation in treatment protocols and possible inclusion in risk stratification. Besides monosomy 7 and large 7p abnormalities encompassing IKZF1, most IKZF1 alterations are short, intragenic deletions. Based on cohorts of patients, we mapped the microdeletion breakpoints and developed a breakpoint-specific fluorescent multiplex polymerase chain reaction that allows detection of recurrent intragenic deletions. This sensitive test could also detect IKZF1 subclonal deletions, whose prognostic significance should be evaluated. Moreover, we show that consensus breakpoint sequences can be used as clonal markers to monitor minimal residual disease. This paper could be useful for translational studies and in clinical management of BCP-ALL.

Published
2013
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19. Impact of genetic abnormalities after allogeneic stem cell transplantation in multiple myeloma: a report of the Société Française de Greffe de Moelle et de Thérapie Cellulaire

Author

Damien Roos-Weil, Philippe Moreau, Hervé Avet-Loiseau, Jean-Louis Golmard, Mathieu Kuentz, Stéphane Vigouroux, Gérard Socié, Sabine Furst, Jean Soulier, Steven Le Gouill, Sylvie François, Anne Thiebaut, Agnès Buzyn, Natacha Maillard, Ibrahim Yakoub-Agha, Nicole Raus, Jean-Paul Fermand, Mauricette Michallet, Didier Blaise, and Nathalie Dhédin

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Background The impact of cytogenetic abnormalities in multiple myeloma after allogeneic stem cell transplantation has not been clearly defined. This study examines whether allogeneic stem cell transplantation could be of benefit for myeloma patients with high-risk cytogenetic abnormalities.Design and Methods This is a retrospective multicenter analysis of the registry of the Société Française de Greffe de Moelle et de Thérapie Cellulaire, including 143 myeloma patients transplanted between 1999 and 2008.Results The incidences of cytogenetic abnormalities were 59% for del(13q), 25% for t(4;14), 25% for del(17p) and 4% for t(14;16). When comparing the population carrying an abnormality to that without the same abnormality, no significant difference was found in progression-free survival, overall survival or progression rate. Patients were grouped according to the presence of any of the poor prognosis cytogenetic abnormalities t(4;14), del(17p) or t(14;16) (n=53) or their absence (n=32). No difference in outcomes was observed between these two groups: the 3-year progression-free survival, overall survival and progression rates were 30% versus 17% (P=0.9), 45% versus 39% (P=0.8) and 53% versus 75% (P=0.9), respectively.Conclusions These data indicate that allogeneic stem cell transplantation could potentially be of benefit to high-risk myeloma patients.

Published
2011
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20. In Vitro and in Vivo Analysis of Endothelial Progenitor Cells from Cryopreserved Umbilical Cord Blood: Are We Ready for Clinical Application?

Author

Valérie Vanneaux, Fida El-Ayoubi, Catherine Delmau, Catherine Driancourt, Séverine Lecourt, Aurore Grelier, Audrey Cras, Wendy Cuccuini, Jean Soulier, Jean-Jacques Lataillade, Marie-Caroline Lebousse-Kerdiles, Jean François Oury, Olivier Sibony, Jean-Pierre Marolleau, Marc Benbunan, Georges Uzan, and Jérôme Larghero

Subjects
Medicine
Abstract

Umbilical cord blood (CB) represents a main source of circulating endothelial progenitor cells (cEPCs). In view of their clinical use, in either the autologous or allogeneic setting, cEPCs should likely be expanded from CB kept frozen in CB banks. In this study, we compared the expansion, functional features, senescence pattern over culture, and in vivo angiogenic potential of cEPCs isolated from fresh or cryopreserved CB (cryoCB). cEPCs could be isolated in only 59% of cryoCB compared to 94% for fresh CB, while CB units were matched in terms of initial volume, nucleated and CD34 + cell number. Moreover, the number of endothelial colony-forming cells was significantly decreased when using cryoCB. Once cEPCs culture was established, the proliferation, migration, tube formation, and acetylated-LDL uptake potentials were similar in both groups. In addition, cEPCs derived from cryoCB displayed the same senescence status and telomeres length as that of cEPCs derived from fresh CB. Karyotypic aberrations were found in cells obtained from both fresh and cryoCB. In vivo, in a hind limb ischemia murine model, cEPCs from fresh and cryoCB were equally efficient to induce neovascularization. Thus, cEPCs isolated from cryoCB exhibited similar properties to those of fresh CB in vitro and in vivo. However, the low frequency of cEPCs colony formation after cryopreservation shed light on the need for specific freezing conditions adapted to cEPCs in view of their future clinical use.

Published
2010
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21. Diagnosis of Fanconi anemia in patients with bone marrow failure

Author

Fernando O. Pinto, Thierry Leblanc, Delphine Chamousset, Gwenaelle Le Roux, Benoit Brethon, Bruno Cassinat, Jérôme Larghero, Jean-Pierre de Villartay, Dominique Stoppa-Lyonnet, André Baruchel, Gérard Socié, Eliane Gluckman, and Jean Soulier

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Background Patients with bone marrow failure and undiagnosed underlying Fanconi anemia may experience major toxicity if given standard-dose conditioning regimens for hematopoietic stem cell transplant. Due to clinical variability and/or potential emergence of genetic reversion with hematopoietic somatic mosaicism, a straightforward Fanconi anemia diagnosis can be difficult to make, and diagnostic strategies combining different assays in addition to classical breakage tests in blood may be needed.Design and Methods We evaluated Fanconi anemia diagnosis on blood lymphocytes and skin fibroblasts from a cohort of 87 bone marrow failure patients (55 children and 32 adults) with no obvious full clinical picture of Fanconi anemia, by performing a combination of chromosomal breakage tests, FANCD2-monoubiquitination assays, a new flow cytometry-based mitomycin C sensitivity test in fibroblasts, and, when Fanconi anemia was diagnosed, complementation group and mutation analyses. The mitomycin C sensitivity test in fibroblasts was validated on control Fanconi anemia and non-Fanconi anemia samples, including other chromosomal instability disorders.Results When this diagnosis strategy was applied to the cohort of bone marrow failure patients, 7 Fanconi anemia patients were found (3 children and 4 adults). Classical chromosomal breakage tests in blood detected 4, but analyses on fibroblasts were necessary to diagnose 3 more patients with hematopoietic somatic mosaicism. Importantly, Fanconi anemia was excluded in all the other patients who were fully evaluated.Conclusions In this large cohort of patients with bone marrow failure our results confirmed that when any clinical/biological suspicion of Fanconi anemia remains after chromosome breakage tests in blood, based on physical examination, history or inconclusive results, then further evaluation including fibroblast analysis should be made. For that purpose, the flow-based mitomycin C sensitivity test here described proved to be a reliable alternative method to evaluate Fanconi anemia phenotype in fibroblasts. This global strategy allowed early and accurate confirmation or rejection of Fanconi anemia diagnosis with immediate clinical impact for those who underwent hematopoietic stem cell transplant.

Published
2009
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22. Rare germline complement factor H variants in patients with paroxysmal nocturnal hemoglobinuria

Author

Pedro Henrique Prata, Jacques-Emmanuel Galimard, Flore Sicre de Fontbrune, Anna Duval, Paula Vieira Martins, Stephane Roncelin, Pierre-Édouard Debureaux, Anne-Claire Lepretre, Lise Larcher, Rudy Birsen, Ygal Benhamou, Jean Soulier, Gérard Socié, Véronique Fremeaux-Bacchi, and Régis Peffault de Latour

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Abstract

Patients with paroxysmal nocturnal hemoglobinuria (PNH) are susceptible to complement-mediated intravascular hemolysis and thrombosis. Factor H (FH) is the main regulator of the complement alternative pathway, which protects cells from unwanted complement-mediated damage. Although FH is not a glycosylphosphatidylinositol-linked molecule, it may play a role in PNH. We sought to determine if rare germline variants in complement factor H (CFH) affect the PNH course, screening 84 patients with PNH treated with eculizumab for rare variants in CFH, CFI, and C3 genes. We compared the allelic frequencies with populational data and a geographically-matched control group, looking for an association between presence of the variants and treatment response (transfusion independence by 6 months). Sixteen patients presented rare variants, 9 in CFH (10.7%). Germline CFH variants were more frequent among patients with PNH than among controls (P = .02) or public data (P < .001) and were more likely to be transfusion-dependent at 6 months after eculizumab initiation (P = .015). With a median follow-up of 5.8 years, 8 of 9 patients with the CFH variant received transfusions, and 2 developed thromboses. None of the patients with the CFH variant had severe aplastic anemia from eculizumab initiation until 6 months. We demonstrated for the first time that rare CFH variants are over-represented among patients with PNH and that germline genetic background may affect the response to eculizumab.

Published
2023

23. Adult Low-Hypodiploid Acute Lymphoblastic Leukemia Emerges from PreleukemicTP53-Mutant Clonal Hematopoiesis

Author

Rathana Kim, Hugo Bergugnat, Lise Larcher, Matthieu Duchmann, Marie Passet, Stéphanie Gachet, Wendy Cuccuini, Marina Lafage-Pochitaloff, Cédric Pastoret, Nathalie Grardel, Vahid Asnafi, Beat W. Schäfer, Eric Delabesse, Raphaël Itzykson, Lionel Adès, Yosr Hicheri, Yves Chalandon, Carlos Graux, Patrice Chevallier, Mathilde Hunault, Thibaut Leguay, Françoise Huguet, Véronique Lhéritier, Hervé Dombret, Jean Soulier, Philippe Rousselot, Nicolas Boissel, Emmanuelle Clappier, Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Pontchaillou [Rennes], Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Necker - Enfants Malades [AP-HP], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Hôpitaux Universitaires de Genève (HUG), Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, R. Kim was a recipient of a PhD grant with financial support from ITMO Cancer of Aviesan on funds administered by INSERM. The study was supported by a grant from Force Hémato (2020). The authors thank the patients and all the GRAALL investigators, physicians, and biologists who contributed samples and data for this study. The authors thank the Saint-Louis Molecular Hematology lab for technical support, especially Hélène Boyer, Emilie Gaudas, Léna Yousfi, and Océanne Richard. The authors also thank Stéphanie Mathis, Pierre Lemaire, and Clémentine Chauvel for the flow cytometry evaluation of ALL diagnostic samples. This work benefited from the genomic platform facility of Institut de Recherche Saint-Louis (IRSL), supported by Association Saint-Louis. This work was supported by THEMA, the national center for precision medicine in leukemia.The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked 'advertisement' in accordance with 18 USC section 1734., UCL - SSS/IREC/MONT - Pôle Mont Godinne, and UCL - (MGD) Service d'hématologie

Subjects
Adult, Aged, 80 and over, Lymphoma, B-Cell, Adolescent, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, General Medicine, Middle Aged, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Aneuploidy, Young Adult, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Mutation, Humans, Prospective Studies, Clonal Hematopoiesis, Tumor Suppressor Protein p53, Aged
Abstract

Low hypodiploidy defines a rare subtype of B-cell acute lymphoblastic leukemia (B-ALL) with a dismal outcome. To investigate the genomic basis of low-hypodiploid ALL (LH-ALL) in adults, we analyzed copy-number aberrations, loss of heterozygosity, mutations, and cytogenetics data in a prospective cohort of Philadelphia (Ph)-negative B-ALL patients (n = 591, ages 18–84 years), allowing us to identify 80 LH-ALL cases (14%). Genomic analysis was critical for evidencing low hypodiploidy in many cases missed by cytogenetics. The proportion of LH-ALL within Ph-negative B-ALL dramatically increased with age, from 3% in the youngest patients (under 40 years old) to 32% in the oldest (over 55 years old). Somatic TP53 biallelic inactivation was the hallmark of adult LH-ALL, present in virtually all cases (98%). Strikingly, we detected TP53 mutations in posttreatment remission samples in 34% of patients. Single-cell proteogenomics of diagnosis and remission bone marrow samples evidenced a preleukemic, multilineage, TP53-mutant clone, reminiscent of age-related clonal hematopoiesis.Significance:We show that low-hypodiploid ALL is a frequent entity within B-ALL in older adults, relying on somatic TP53 biallelic alteration. Our study unveils a link between aging and low-hypodiploid ALL, with TP53-mutant clonal hematopoiesis representing a preleukemic reservoir that can give rise to aneuploidy and B-ALL.See related commentary by Saiki and Ogawa, p. 102.This article is highlighted in the In This Issue feature, p. 101

Published
2023

24. Clinical and Molecular Determinants of Clonal Evolution in Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria

Author

Carmelo Gurnari, Simona Pagliuca, Pedro Henrique Prata, Jacques-Emmanuel Galimard, Luiz Fernando B. Catto, Lise Larcher, Marie Sebert, Vincent Allain, Bhumika J. Patel, Arda Durmaz, Andre L. Pinto, Mariana C.B. Inacio, Lucie Hernandez, Nathalie Dhedin, Sophie Caillat-Zucman, Emmanuelle Clappier, Flore Sicre de Fontbrune, Maria Teresa Voso, Valeria Visconte, Régis Peffault de Latour, Jean Soulier, Rodrigo T. Calado, Gérard Socié, and Jaroslaw P. Maciejewski

Subjects
Cancer Research, Oncology, Settore MED/15
Abstract

PURPOSE Secondary myeloid neoplasms (sMNs) remain the most serious long-term complications in patients with aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH). However, sMNs lack specific predictors, dedicated surveillance measures, and early therapeutic interventions. PATIENTS AND METHODS We studied a multicenter, retrospective cohort of 1,008 patients (median follow-up 8.6 years) with AA and PNH to assess clinical and molecular determinants of clonal evolution. RESULTS Although none of the patients transplanted upfront (n = 117) developed clonal complications (either sMN or secondary PNH), the 10-year cumulative incidence of sMN in nontransplanted cases was 11.6%. In severe AA, older age at presentation and lack of response to immunosuppressive therapy were independently associated with increased risk of sMN, whereas untreated patients had the highest risk among nonsevere cases. The elapsed time from AA to sMN was 4.5 years. sMN developed in 94 patients. The 5-year overall survival reached 40% and was independently associated with bone marrow blasts at sMN onset. Myelodysplastic syndrome with high-risk phenotypes, del7/7q, and ASXL1, SETBP1, RUNX1, and RAS pathway gene mutations were the most frequent characteristics. Cross-sectional studies of clonal dynamics from baseline to evolution revealed that PIGA/human leukocyte antigen lesions decreased over time, being replaced by clones with myeloid hits. PIGA and BCOR/L1 mutation carriers had a lower risk of sMN progression, whereas myeloid driver lesions marked the group with a higher risk. CONCLUSION The risk of sMN in AA is associated with disease severity, lack of response to treatment, and patients' age. sMNs display high-risk morphological, karyotypic, and molecular features. The landscape of acquired somatic mutations is complex and incompletely understood and should be considered with caution in medical management.

Published
2023

25. Prognostic impact of DDX41 germline mutations in intensively treated acute myeloid leukemia patients: an ALFA-FILO study

Author

Nicolas Duployez, Laëtitia Largeaud, Matthieu Duchmann, Rathana Kim, Julie Rieunier, Juliette Lambert, Audrey Bidet, Lise Larcher, Jean Lemoine, François Delhommeau, Pierre Hirsch, Laurène Fenwarth, Olivier Kosmider, Justine Decroocq, Anne Bouvier, Yannick Le Bris, Marlène Ochmann, Alberto Santagostino, Lionel Adès, Pierre Fenaux, Xavier Thomas, Jean-Baptiste Micol, Claude Gardin, Raphael Itzykson, Jean Soulier, Emmanuelle Clappier, Christian Recher, Claude Preudhomme, Arnaud Pigneux, Hervé Dombret, Eric Delabesse, and Marie Sébert

Subjects
Male, Immunology, Hematopoietic Stem Cell Transplantation, Cell Biology, Hematology, Prognosis, Biochemistry, DEAD-box RNA Helicases, Leukemia, Myeloid, Acute, Humans, Female, Prospective Studies, Germ-Line Mutation, Retrospective Studies
Abstract

DDX41 germline mutations (DDX41MutGL) are the most common genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia (AML). Recent reports suggest that DDX41MutGL myeloid malignancies could be considered as a distinct entity, even if their specific presentation and outcome remain to be defined. We describe here the clinical and biological features of 191 patients with DDX41MutGL AML. Baseline characteristics and outcome of 86 of these patients, treated with intensive chemotherapy in 5 prospective Acute Leukemia French Association/French Innovative Leukemia Organization trials, were compared with those of 1604 patients with DDX41 wild-type (DDX41WT) AML, representing a prevalence of 5%. Patients with DDX41MutGL AML were mostly male (75%), in their seventh decade, and with low leukocyte count (median, 2 × 109/L), low bone marrow blast infiltration (median, 33%), normal cytogenetics (75%), and few additional somatic mutations (median, 2). A second somatic DDX41 mutation (DDX41MutSom) was found in 82% of patients, and clonal architecture inference suggested that it could be the main driver for AML progression. DDX41MutGL patients displayed higher complete remission rates (94% vs 69%; P < .0001) and longer restricted mean overall survival censored at hematopoietic stem cell transplantation (HSCT) than 2017 European LeukemiaNet intermediate/adverse (Int/Adv) DDX41WT patients (5-year difference in restricted mean survival times, 13.6 months; P < .001). Relapse rates censored at HSCT were lower at 1 year in DDX41MutGL patients (15% vs 44%) but later increased to be similar to Int/Adv DDX41WT patients at 3 years (82% vs 75%). HSCT in first complete remission was associated with prolonged relapse-free survival (hazard ratio, 0.43; 95% confidence interval, 0.21-0.88; P = .02) but not with longer overall survival (hazard ratio, 0.77; 95% confidence interval, 0.35-1.68; P = .5).

Published
2022

26. IPSS-M in myelodysplastic neoplasms arising from aplastic anemia and paroxysmal nocturnal hemoglobinuria

Author

Carmelo Gurnari, Pedro Henrique Prata, Luiz Fernando B. Catto, Arda Durmaz, Lise Larcher, Marie Sébert, Vincent Allain, Tariq Kewan, Simona Pagliuca, André Luiz Pinto, Mariana C. B. Inacio, Lucie Hernandez, Nathalie Dhedin, Sophie Caillat-Zucman, Emmanuelle Clappier, Flore Sicre de Fontbrune, Maria Teresa Voso, Valeria Visconte, Régis Peffault de Latour, Jean Soulier, Gérard Socie, Rodrigo T. Calado, and Jaroslaw P. Maciejewski

Subjects
Immunology, Cell Biology, Hematology, Settore MED/15, Biochemistry
Published
2023

27. Supplementary Figures S1-S10 from Adult Low-Hypodiploid Acute Lymphoblastic Leukemia Emerges from Preleukemic TP53-Mutant Clonal Hematopoiesis

Author

Emmanuelle Clappier, Nicolas Boissel, Philippe Rousselot, Jean Soulier, Hervé Dombret, Véronique Lhéritier, Françoise Huguet, Thibaut Leguay, Mathilde Hunault, Patrice Chevallier, Carlos Graux, Yves Chalandon, Yosr Hicheri, Lionel Adès, Raphaël Itzykson, Eric Delabesse, Beat W. Schäfer, Vahid Asnafi, Nathalie Grardel, Cédric Pastoret, Marina Lafage-Pochitaloff, Wendy Cuccuini, Stéphanie Gachet, Marie Passet, Matthieu Duchmann, Lise Larcher, Hugo Bergugnat, and Rathana Kim

Abstract

Supplementary figure 1. Sequencing-based analysis of CNA and LOH in adult LH-ALL. Supplementary figure 2. Representation of mutations in the frequent targeted genes in adult LH-ALL. Supplementary figure 3. Longitudinal assessment of TP53-mutant cell fraction as determined by ddPCR along with clonal IG/TR-based MRD quantification in three patients with undetectable TP53 mutation at remission. Supplementary figure 4. Merged single-cell analysis of cell-surface markers by ADT-sequencing of remission samples from three LH-ALL patients. Supplementary figure 5. Individual single-cell analyses of cell-surface markers by ADT-sequencing of remission samples from three LH-ALL patients. Supplementary figure 6. Individual analyses of single-cell immunophenotyping and genotyping of remission samples from three LH-ALL patients. Supplementary figure 7. Evaluation of allelic dropout rate on heterozygous single nucleotide polymorphism (SNPs) in remission samples. Supplementary figure 8. Individual single-cell analysis of cell-surface markers by ADT-sequencing of diagnosis samples from three LH-ALL patients. Supplementary figure 9. Single-cell genotyping of heterozygous SNPs allowing LOH assessment in diagnosis samples from three LH-ALL patients. Supplementary Figure 10. Distribution of single-cell genotypes of two LH-ALL patients with persistent TP53 and JAK2 (EI_046) or DNMT3A (EI_035) mutations in remission samples.

Published
2023

28. Data from A Tumor Suppressor Enhancer of PTEN in T-cell Development and Leukemia

Author

Daniel Herranz, Pedro P. Rocha, Hossein Khiabanian, Charles G. Mullighan, Pieter Van Vlierberghe, Tom Taghon, Jean Soulier, Jules P.P. Meijerink, Manel Esteller, Rico Hagelaar, Carlos A. García-Prieto, Stéphanie Gachet, Shirley Luo, Victoria da Silva-Diz, Matthew A. Lawlor, Steven Strubbe, Anna Kuchmiy, Juliette Roels, Shunsuke Kimura, Amartya Singh, Jui-Wan Loh, Olga Lancho, and Luca Tottone

Abstract

Long-range oncogenic enhancers play an important role in cancer. Yet, whether similar regulation of tumor suppressor genes is relevant remains unclear. Loss of expression of PTEN is associated with the pathogenesis of various cancers, including T-cell acute lymphoblastic leukemia (T-ALL). Here, we identify a highly conserved distal enhancer (PE) that interacts with the PTEN promoter in multiple hematopoietic populations, including T cells, and acts as a hub of relevant transcription factors in T-ALL. Consistently, loss of PE leads to reduced PTEN levels in T-ALL cells. Moreover, PE-null mice show reduced Pten levels in thymocytes and accelerated development of NOTCH1-induced T-ALL. Furthermore, secondary loss of PE in established leukemias leads to accelerated progression and a gene expression signature driven by Pten loss. Finally, we uncovered recurrent deletions encompassing PE in T-ALL, which are associated with decreased PTEN levels. Altogether, our results identify PE as the first long-range tumor suppressor enhancer directly implicated in cancer.Significance:Here, we identify a PTEN enhancer that is recurrently deleted in patients with T-ALL. Loss of this enhancer leads to reduced PTEN levels in T cells together with accelerated generation and progression of NOTCH1-induced leukemia in vivo. These results uncover long-range regulation of tumor suppressor genes as a relevant mechanism in cancer.This article is highlighted in the In This Issue feature, p. 1

Published
2023

29. Supplementary Tables S1-S11 from Adult Low-Hypodiploid Acute Lymphoblastic Leukemia Emerges from Preleukemic TP53-Mutant Clonal Hematopoiesis

Author

Emmanuelle Clappier, Nicolas Boissel, Philippe Rousselot, Jean Soulier, Hervé Dombret, Véronique Lhéritier, Françoise Huguet, Thibaut Leguay, Mathilde Hunault, Patrice Chevallier, Carlos Graux, Yves Chalandon, Yosr Hicheri, Lionel Adès, Raphaël Itzykson, Eric Delabesse, Beat W. Schäfer, Vahid Asnafi, Nathalie Grardel, Cédric Pastoret, Marina Lafage-Pochitaloff, Wendy Cuccuini, Stéphanie Gachet, Marie Passet, Matthieu Duchmann, Lise Larcher, Hugo Bergugnat, and Rathana Kim

Abstract

Supplementary Table 1. Karyotypes of LH-ALL patients at diagnosis. Supplementary Table 2. Somatic variants detected in LH-ALL patients at diagnosis. Supplementary Table 3. ARCH related variants detected in LH-ALL patients at remission. Supplementary Table 4. Minimal residual disease values of remission samples used for mutation analysis. Supplementary Table 5. Somatic alterations in cell populations from diagnostic samples (BMMC) based on single-cell analyses. Supplementary Table 6. Somatic alterations in FACS-sorted cell populations from diagnostic samples. Supplementary Table 7. Panel of genes for targeted sequencing. Supplementary Table 8. Single cell DNA amplicons for genotyping and LOH analyses. Supplementary Table 9. Single cell DNA amplicons for B-ALL clono-specific IG/TR detection. Supplementary Table 10. ADT-seq panel and spike-in antibodies. Supplementary Table 11. Single cell sequencing metrics.

Published
2023

30. Supplementary Information from A Tumor Suppressor Enhancer of PTEN in T-cell Development and Leukemia

Author

Daniel Herranz, Pedro P. Rocha, Hossein Khiabanian, Charles G. Mullighan, Pieter Van Vlierberghe, Tom Taghon, Jean Soulier, Jules P.P. Meijerink, Manel Esteller, Rico Hagelaar, Carlos A. García-Prieto, Stéphanie Gachet, Shirley Luo, Victoria da Silva-Diz, Matthew A. Lawlor, Steven Strubbe, Anna Kuchmiy, Juliette Roels, Shunsuke Kimura, Amartya Singh, Jui-Wan Loh, Olga Lancho, and Luca Tottone

Abstract

Supplementary Figures and Tables combined

Published
2023

31. Data from Adult Low-Hypodiploid Acute Lymphoblastic Leukemia Emerges from Preleukemic TP53-Mutant Clonal Hematopoiesis

Author

Emmanuelle Clappier, Nicolas Boissel, Philippe Rousselot, Jean Soulier, Hervé Dombret, Véronique Lhéritier, Françoise Huguet, Thibaut Leguay, Mathilde Hunault, Patrice Chevallier, Carlos Graux, Yves Chalandon, Yosr Hicheri, Lionel Adès, Raphaël Itzykson, Eric Delabesse, Beat W. Schäfer, Vahid Asnafi, Nathalie Grardel, Cédric Pastoret, Marina Lafage-Pochitaloff, Wendy Cuccuini, Stéphanie Gachet, Marie Passet, Matthieu Duchmann, Lise Larcher, Hugo Bergugnat, and Rathana Kim

Abstract

Low hypodiploidy defines a rare subtype of B-cell acute lymphoblastic leukemia (B-ALL) with a dismal outcome. To investigate the genomic basis of low-hypodiploid ALL (LH-ALL) in adults, we analyzed copy-number aberrations, loss of heterozygosity, mutations, and cytogenetics data in a prospective cohort of Philadelphia (Ph)-negative B-ALL patients (n = 591, ages 18–84 years), allowing us to identify 80 LH-ALL cases (14%). Genomic analysis was critical for evidencing low hypodiploidy in many cases missed by cytogenetics. The proportion of LH-ALL within Ph-negative B-ALL dramatically increased with age, from 3% in the youngest patients (under 40 years old) to 32% in the oldest (over 55 years old). Somatic TP53 biallelic inactivation was the hallmark of adult LH-ALL, present in virtually all cases (98%). Strikingly, we detected TP53 mutations in posttreatment remission samples in 34% of patients. Single-cell proteogenomics of diagnosis and remission bone marrow samples evidenced a preleukemic, multilineage, TP53-mutant clone, reminiscent of age-related clonal hematopoiesis.Significance:We show that low-hypodiploid ALL is a frequent entity within B-ALL in older adults, relying on somatic TP53 biallelic alteration. Our study unveils a link between aging and low-hypodiploid ALL, with TP53-mutant clonal hematopoiesis representing a preleukemic reservoir that can give rise to aneuploidy and B-ALL.See related commentary by Saiki and Ogawa, p. 102.This article is highlighted in the In This Issue feature, p. 101

Published
2023

32. supplementary table S2 from HOXA9 Cooperates with Activated JAK/STAT Signaling to Drive Leukemia Development

Author

Jan Cools, Enrico Radaelli, Olli Lohi, Maria Bouvy-Liivrand, Susanna Teppo, Merja Heinäniemi, Jules P. Meijerink, Jean Soulier, Rik Gijsbers, Simon Bornschein, Ellen Geerdens, Antonis Dagklis, Marlies Vanden Bempt, Carmen Vicente, Roel Vandepoel, Olga Gielen, Bram Sweron, Delphine Verbeke, Sandrine Degryse, Sofie Demeyer, and Charles E. de Bock

Abstract

supplementary table (excel)

Published
2023

33. Key Resources Table from Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy

Author

Hugues de Thé, Maria Paola Martelli, Keisuke Ito, Brunangelo Falini, Ali Bazarbachi, Valérie Lallemand-Breitenbach, Tak W. Mak, Lorenzo Brunetti, Guido Kroemer, Olivier Espeli, Pierre Fenaux, Hervé Dombret, Raphael Itzykson, Lionel Ades, Emmanuel Raffoux, Hiba El Hajj, Pierre Rustin, Paule Bénit, Jennifer J. Trowbridge, Sylvère Durand, Jean Soulier, Stéphanie Gachet, Sylvie Souquere, Emmanuelle Clappier, Marie Sebert, Sylvie Rimsky, Lidio Conte, Chengchen Wu, Claudia Morganti, Shirine Benhenda, Samuel Quentin, Takashi Sakamoto, Rita Hleihel, Caroline Berthier, Domitille Rérolle, and Hsin-Chieh Wu

Abstract

Key resource table with RRID

Published
2023

34. Table S3 from Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy

Author

Hugues de Thé, Maria Paola Martelli, Keisuke Ito, Brunangelo Falini, Ali Bazarbachi, Valérie Lallemand-Breitenbach, Tak W. Mak, Lorenzo Brunetti, Guido Kroemer, Olivier Espeli, Pierre Fenaux, Hervé Dombret, Raphael Itzykson, Lionel Ades, Emmanuel Raffoux, Hiba El Hajj, Pierre Rustin, Paule Bénit, Jennifer J. Trowbridge, Sylvère Durand, Jean Soulier, Stéphanie Gachet, Sylvie Souquere, Emmanuelle Clappier, Marie Sebert, Sylvie Rimsky, Lidio Conte, Chengchen Wu, Claudia Morganti, Shirine Benhenda, Samuel Quentin, Takashi Sakamoto, Rita Hleihel, Caroline Berthier, Domitille Rérolle, and Hsin-Chieh Wu

Abstract

Supplementary table S3

Published
2023

35. Table S3 from Deletion 6q Drives T-cell Leukemia Progression by Ribosome Modulation

Author

Jean Soulier, François Sigaux, Hugues de Thé, Claude Gazin, Jean-Jacques Diaz, Emmanuelle Clappier, Hervé Dombret, André Baruchel, Jules P. Meijerink, Pieter Van Vlierberghe, Tom Taghon, Isabelle André-Schmutz, Gerben Menschaert, Wouter Van Loocke, Jessica G. Buijs-Gladdines, Willem K. Smits, Marika Pla, Lucie Hernandez, Godelieve Meunier, Delphine Briot, Gabriel Thérizols, Marc Delord, Samuel Quentin, Frédéric Catez, Eulalia Genesca, David Avran, Tiama El-Chaar, and Stéphanie Gachet

Abstract

Differentially Expressed Proteins Deleted versus non-deleted clones

Published
2023

36. supplementary figure S3 from Noninvasive Molecular Screening for Oral Precancer in Fanconi Anemia Patients

Author

Ruud H. Brakenhoff, Boudewijn J.M. Braakhuis, C. René Leemans, Jean Soulier, Dorly J.H. Deeg, Marijke Buijze, Arjen Brink, Thijs Wu, Ralf Dietrich, Eunike Velleuer, and Stephanie E. Smetsers

Abstract

Figure S3. Visible lesions in non-transplanted FA patients. Visible lesions were found in 27 of 110 patients (25%) with follow-up. Five patients with visible lesions (4 with LOH, 1 without LOH) developed HNSCC.

Published
2023

37. Data from Noninvasive Molecular Screening for Oral Precancer in Fanconi Anemia Patients

Author

Ruud H. Brakenhoff, Boudewijn J.M. Braakhuis, C. René Leemans, Jean Soulier, Dorly J.H. Deeg, Marijke Buijze, Arjen Brink, Thijs Wu, Ralf Dietrich, Eunike Velleuer, and Stephanie E. Smetsers

Abstract

LOH at chromosome arms 3p, 9p, 11q, and 17p are well-established oncogenetic aberrations in oral precancerous lesions and promising biomarkers to monitor the development of oral cancer. Noninvasive LOH screening of brushed oral cells is a preferable method for precancer detection in patients at increased risk for head and neck squamous cell carcinoma (HNSCC), such as patients with Fanconi anemia. We determined the prevalence of LOH in brushed samples of the oral epithelium of 141 patients with Fanconi anemia and 144 aged subjects, and studied the association between LOH and HNSCC. LOH was present in 14 (9.9%) nontransplanted patients with Fanconi anemia, whereas LOH was not detected in a low-risk group (n = 50, >58 years, nonsmoking/nonalcohol history) and a group with somewhat increased HNSCC risk (n = 94, >58 years, heavy smoking/excessive alcohol use); Fisher exact test, P = 0.023 and P = 0.001, respectively. Most frequent genetic alteration was LOH at 9p. Age was a significant predictor of LOH (OR, 1.13, P = 0.001). Five patients with Fanconi anemia developed HNSCC during the study at a median age of 39.6 years (range, 24.8–53.7). LOH was significantly associated with HNSCC (Fisher exact test, P = 0.000). Unexpectedly, the LOH assay could not be used for transplanted patients with Fanconi anemia because donor DNA in brushed oral epithelium, most likely from donor leukocytes present in the oral cavity, disturbed the analysis. Noninvasive screening using a LOH assay on brushed samples of the oral epithelium has a promising outlook in patients with Fanconi anemia. However, assays need to be adapted in case of stem cell transplantation, because of contaminating donor DNA. Cancer Prev Res; 8(11); 1102–11. ©2015 AACR.

Published
2023

38. Data from Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy

Author

Hugues de Thé, Maria Paola Martelli, Keisuke Ito, Brunangelo Falini, Ali Bazarbachi, Valérie Lallemand-Breitenbach, Tak W. Mak, Lorenzo Brunetti, Guido Kroemer, Olivier Espeli, Pierre Fenaux, Hervé Dombret, Raphael Itzykson, Lionel Ades, Emmanuel Raffoux, Hiba El Hajj, Pierre Rustin, Paule Bénit, Jennifer J. Trowbridge, Sylvère Durand, Jean Soulier, Stéphanie Gachet, Sylvie Souquere, Emmanuelle Clappier, Marie Sebert, Sylvie Rimsky, Lidio Conte, Chengchen Wu, Claudia Morganti, Shirine Benhenda, Samuel Quentin, Takashi Sakamoto, Rita Hleihel, Caroline Berthier, Domitille Rérolle, and Hsin-Chieh Wu

Abstract

Acute myeloid leukemia (AML) pathogenesis often involves a mutation in the NPM1 nucleolar chaperone, but the bases for its transforming properties and overall association with favorable therapeutic responses remain incompletely understood. Here we demonstrate that an oncogenic mutant form of NPM1 (NPM1c) impairs mitochondrial function. NPM1c also hampers formation of promyelocytic leukemia (PML) nuclear bodies (NB), which are regulators of mitochondrial fitness and key senescence effectors. Actinomycin D (ActD), an antibiotic with unambiguous clinical efficacy in relapsed/refractory NPM1c-AMLs, targets these primed mitochondria, releasing mitochondrial DNA, activating cyclic GMP-AMP synthase signaling, and boosting reactive oxygen species (ROS) production. The latter restore PML NB formation to drive TP53 activation and senescence of NPM1c-AML cells. In several models, dual targeting of mitochondria by venetoclax and ActD synergized to clear AML and prolong survival through targeting of PML. Our studies reveal an unexpected role for mitochondria downstream of NPM1c and implicate a mitochondrial/ROS/PML/TP53 senescence pathway as an effector of ActD-based therapies.Significance:ActD induces complete remissions in NPM1-mutant AMLs. We found that NPM1c affects mitochondrial biogenesis and PML NBs. ActD targets mitochondria, yielding ROS which enforce PML NB biogenesis and restore senescence. Dual targeting of mitochondria with ActD and venetoclax sharply potentiates their anti-AML activities in vivo.This article is highlighted in the In This Issue feature, p. 2945

Published
2023

39. Supplementary Data from Deletion 6q Drives T-cell Leukemia Progression by Ribosome Modulation

Author

Jean Soulier, François Sigaux, Hugues de Thé, Claude Gazin, Jean-Jacques Diaz, Emmanuelle Clappier, Hervé Dombret, André Baruchel, Jules P. Meijerink, Pieter Van Vlierberghe, Tom Taghon, Isabelle André-Schmutz, Gerben Menschaert, Wouter Van Loocke, Jessica G. Buijs-Gladdines, Willem K. Smits, Marika Pla, Lucie Hernandez, Godelieve Meunier, Delphine Briot, Gabriel Thérizols, Marc Delord, Samuel Quentin, Frédéric Catez, Eulalia Genesca, David Avran, Tiama El-Chaar, and Stéphanie Gachet

Abstract

Supp Fig. S1-6, Supp Tables S1-S3, Supp Methods and References

Published
2023

40. Supplementary Figures and Methods from Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy

Author

Hugues de Thé, Maria Paola Martelli, Keisuke Ito, Brunangelo Falini, Ali Bazarbachi, Valérie Lallemand-Breitenbach, Tak W. Mak, Lorenzo Brunetti, Guido Kroemer, Olivier Espeli, Pierre Fenaux, Hervé Dombret, Raphael Itzykson, Lionel Ades, Emmanuel Raffoux, Hiba El Hajj, Pierre Rustin, Paule Bénit, Jennifer J. Trowbridge, Sylvère Durand, Jean Soulier, Stéphanie Gachet, Sylvie Souquere, Emmanuelle Clappier, Marie Sebert, Sylvie Rimsky, Lidio Conte, Chengchen Wu, Claudia Morganti, Shirine Benhenda, Samuel Quentin, Takashi Sakamoto, Rita Hleihel, Caroline Berthier, Domitille Rérolle, and Hsin-Chieh Wu

Abstract

Supplementary figures and methods

Published
2023

41. Supplemental tables and figures from HOXA9 Cooperates with Activated JAK/STAT Signaling to Drive Leukemia Development

Author

Jan Cools, Enrico Radaelli, Olli Lohi, Maria Bouvy-Liivrand, Susanna Teppo, Merja Heinäniemi, Jules P. Meijerink, Jean Soulier, Rik Gijsbers, Simon Bornschein, Ellen Geerdens, Antonis Dagklis, Marlies Vanden Bempt, Carmen Vicente, Roel Vandepoel, Olga Gielen, Bram Sweron, Delphine Verbeke, Sandrine Degryse, Sofie Demeyer, and Charles E. de Bock

Abstract

Supplemental tables and figures

Published
2023

43. Data from Deletion 6q Drives T-cell Leukemia Progression by Ribosome Modulation

Author

Jean Soulier, François Sigaux, Hugues de Thé, Claude Gazin, Jean-Jacques Diaz, Emmanuelle Clappier, Hervé Dombret, André Baruchel, Jules P. Meijerink, Pieter Van Vlierberghe, Tom Taghon, Isabelle André-Schmutz, Gerben Menschaert, Wouter Van Loocke, Jessica G. Buijs-Gladdines, Willem K. Smits, Marika Pla, Lucie Hernandez, Godelieve Meunier, Delphine Briot, Gabriel Thérizols, Marc Delord, Samuel Quentin, Frédéric Catez, Eulalia Genesca, David Avran, Tiama El-Chaar, and Stéphanie Gachet

Abstract

Deletion of chromosome 6q is a well-recognized abnormality found in poor-prognosis T-cell acute lymphoblastic leukemia (T-ALL). Using integrated genomic approaches, we identified two candidate haploinsufficient genes contiguous at 6q14, SYNCRIP (encoding hnRNP-Q) and SNHG5 (that hosts snoRNAs), both involved in regulating RNA maturation and translation. Combined silencing of both genes, but not of either gene alone, accelerated leukemogeneis in a Tal1/Lmo1/Notch1-driven mouse model, demonstrating the tumor-suppressive nature of the two-gene region. Proteomic and translational profiling of cells in which we engineered a short 6q deletion by CRISPR/Cas9 genome editing indicated decreased ribosome and mitochondrial activities, suggesting that the resulting metabolic changes may regulate tumor progression. Indeed, xenograft experiments showed an increased leukemia-initiating cell activity of primary human leukemic cells upon coextinction of SYNCRIP and SNHG5. Our findings not only elucidate the nature of 6q deletion but also highlight the role of ribosomes and mitochondria in T-ALL tumor progression.Significance:The oncogenic role of 6q deletion in T-ALL has remained elusive since this chromosomal abnormality was first identified more than 40 years ago. We combined genomic analysis and functional models to show that the codeletion of two contiguous genes at 6q14 enhances malignancy through deregulation of a ribosome–mitochondria axis, suggesting the potential for therapeutic intervention.This article is highlighted in the In This Issue feature, p. 1494

Published
2023

44. UBTF tandem duplications define a distinct subtype of adult de novo acute myeloid leukemia

Author

Nicolas Duployez, Loïc Vasseur, Rathana Kim, Laëtitia Largeaud, Marie Passet, Anaïs L’Haridon, Pierre Lemaire, Laurène Fenwarth, Sandrine Geffroy, Nathalie Helevaut, Karine Celli‑Lebras, Lionel Adès, Delphine Lebon, Céline Berthon, Alice Marceau-Renaut, Meyling Cheok, Juliette Lambert, Christian Récher, Emmanuel Raffoux, Jean-Baptiste Micol, Arnaud Pigneux, Claude Gardin, Eric Delabesse, Jean Soulier, Mathilde Hunault, Hervé Dombret, Raphael Itzykson, Emmanuelle Clappier, Claude Preudhomme, Service de pathologie [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT), Centre de Recherches en Cancérologie de Toulouse (CRCT), 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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité (UPCité), CHU Amiens-Picardie, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL), Thérapie génique et contrôle de l'expansion cellulaire (UMR E007), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service d'hématologie adulte [Hôpital de Saint Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Hôpital Haut-Lévêque, and Université Sciences et Technologies - Bordeaux 1 (UB)-CHU Bordeaux [Bordeaux]

Subjects
Cancer Research, Oncology, Hematology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Tandem duplications (TDs) of the UBTF gene have been recently described as a recurrent alteration in pediatric acute myeloid leukemia (AML). Here, by screening 1946 newly diagnosed adult AML, we found that UBTF-TDs occur in about 3% of patients aged 18–60 years, in a mutually exclusive pattern with other known AML subtype-defining alterations. The characteristics of 59 adults with UBTF-TD AML included young age (median 37 years), low bone marrow (BM) blast infiltration (median 25%), and high rates of WT1 mutations (61%), FLT3-ITDs (51%) and trisomy 8 (29%). BM morphology frequently demonstrates dysmyelopoiesis albeit modulated by the co-occurrence of FLT3-ITD. UBTF-TD patients have lower complete remission (CR) rates (57% after 1 course and 76% after 2 courses of intensive chemotherapy [ICT]) than UBTF-wild-type patients. In patients enrolled in the ALFA-0702 study (n = 614 patients including 21 with UBTF-TD AML), the 3-year disease-free survival (DFS) and overall survival of UBTF-TD patients were 42.9% (95%CI: 23.4–78.5%) and 57.1% (95%CI: 39.5–82.8%) and did not significantly differ from those of ELN 2022 intermediate/adverse risk patients. Finally, the study of paired diagnosis and relapsed/refractory AML samples suggests that WT1-mutated clones are frequently selected under ICT. This study supports the recognition of UBTF-TD AML as a new AML entity in adults.

Published
2023

45. 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

46. Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria

Author

Jérémie Rosain, Anna-Lena Neehus, Jérémy Manry, Rui Yang, Jérémie Le Pen, Wassim Daher, Zhiyong Liu, Yi-Hao Chan, Natalia Tahuil, Özden Türel, Mathieu Bourgey, Masato Ogishi, Jean-Marc Doisne, Helena M. Izquierdo, Takayoshi Shirasaki, Tom Le Voyer, Antoine Guérin, Paul Bastard, Marcela Moncada-Vélez, Ji Eun Han, Taushif Khan, Franck Rapaport, Seon-Hui Hong, Andrew Cheung, Kathrin Haake, Barbara C. Mindt, Laura Pérez, Quentin Philippot, Danyel Lee, Peng Zhang, Darawan Rinchai, Fatima Al Ali, Manar Mahmoud Ahmad Ata, Mahbuba Rahman, Jessica N. Peel, Søren Heissel, Henrik Molina, Yasemin Kendir-Demirkol, Rasheed Bailey, Shuxiang Zhao, Jonathan Bohlen, Mathieu Mancini, Yoann Seeleuthner, Marie Roelens, Lazaro Lorenzo, Camille Soudée, María Elvira Josefina Paz, María Laura González, Mohamed Jeljeli, Jean Soulier, Serge Romana, Anne-Sophie L’Honneur, Marie Materna, Rubén Martínez-Barricarte, Mathieu Pochon, Carmen Oleaga-Quintas, Alexandre Michev, Mélanie Migaud, Romain Lévy, Marie-Alexandra Alyanakian, Flore Rozenberg, Carys A. Croft, Guillaume Vogt, Jean-François Emile, Laurent Kremer, Cindy S. Ma, Jörg H. Fritz, Stanley M. Lemon, András N. Spaan, Nicolas Manel, Laurent Abel, Margaret R. MacDonald, Stéphanie Boisson-Dupuis, Nico Marr, Stuart G. Tangye, James P. Di Santo, Qian Zhang, Shen-Ying Zhang, Charles M. Rice, Vivien Béziat, Nico Lachmann, David Langlais, Jean-Laurent Casanova, Philippe Gros, Jacinta Bustamante, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hannover Medical School [Hannover] (MHH), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Institut de Recherche en Infectiologie de Montpellier (IRIM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Yong Loo Lin School of Medicine [Singapore], Hospital del Niño Jesus, San Miguel de Tucumán, Bezmiâlem Vakıf Üniversitesi, McGill University = Université McGill [Montréal, Canada], Immunité Innée - Innate Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Curie [Paris], University of North Carolina System (UNC), Garvan Institute of medical research, The University of Sydney, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Universidad de Antioquia = University of Antioquia [Medellín, Colombia], East China Normal University [Shangaï] (ECNU), Sidra Medicine [Doha, Qatar], 'Juan Pedro Garrahan' National Hospital of Pediatrics, Buenos Aires, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Cochin [AP-HP], Hopital Saint-Louis [AP-HP] (AP-HP), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Hôpital Ambroise Paré [AP-HP], Université de Montpellier (UM), Howard Hughes Medical Institute (HHMI), The Laboratory of Human Genetics of Infectious Diseases is supported in part by grants from Inserm, Paris Cité University, the St. Giles Foundation, The Rockefeller University, the Center for Clinical and Translational Science (UL1TR001866), the National Center for Research Resources and the National Center for Advancing Sciences, the National Institutes of Health (NIH), (R01AI095983, R01AI088364, R01AI163029, and U19AI162568), the National Institute of Allergy and Infectious Diseases, the French National Research Agency (ANR) under the 'Investments for the future' program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the ANRS Nord-Sud (ANRS-COV05), ANRS (ECTZ170784-ANRS0073), GENVIR (ANR-20-CE93-003), GENMSMD (ANR-16-CE17-0005-01), AABIFNCOV (ANR-20-CO11-0001), GenMIS-C (ANR-21-COVR-0039), SUNLIVE (ANR-19-CE15-0012-01), MAFMACRO (ANR-22-CE92-0008) grants, Ecos-NORD (ECOS N°C19S01), the Fisher Center for Alzheimer's Research Foundation, the Meyer Foundation, the JPB Foundation, the European Union’s Horizon 2020 research and innovation program (824110, EASI-Genomics), the Square Foundation, Grandir–Fonds de solidarité pour l’Enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, the French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19), and REACTing-INSERM. The Laboratory of Virology and Infectious Disease was supported in part by the NIH (R01AI091707-10 to C.M.R.). J.L.P. was supported by the Francois Wallace Monahan Postdoctoral Fellowship at The Rockefeller University and the European Molecular Biology Organization Long-Term Fellowship (ALTF 380-2018). N. Marr was supported by Sidra Medicine and the Qatar National Research Fund (NPRP9-251-3-045). The Yale Center for Mendelian Genomics (UM1HG006504) was funded by the National Human Genome Research Institute, the Yale GSP Coordinating Center (U24 HG008956), and the Yale High-Performance Computing Center (S10OD018521). This research was partly supported by Calcul Québec, Compute Canada Canadian Institutes of Health Research (CIHR) Project Grant to D. Langlais. (#168959) and a CIHR Foundation Grant (to P.G.). D. Langlais was also supported by an FRQS Chercheur-Boursier Junior 1 Award and the Calgary Foundation for Innovation John R. Evans Leaders Fund. P.G. is supported by a Distinguished James McGill Professorship award from McGill University. S.M.L is supported by the NIH: R01-AI103083 and R01-AI150095. J.R. was supported by poste d’accueil Inserm'. J.R., P.B., and T.L.V were supported by the MD-PhD program of the Imagine Institute by the Bettencourt Schueller Foundation. N.L received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (852178 grant), German Research Foundation,(DFG) under Germany’s Excellence Strategy—EXC 2155—project number 390874280 and REBIRTH 'Förderung aus Mitteln des Niedersächsischen Vorab'. A.-L.N. was supported by the international PhD program of the Imagine Institute, by the Bettencourt Schueller Foundation and the fin de thèse FRM program (FDT202204015102). R.Y. was supported by the Sackler Center for Biomedicine and Nutrition, the Shapiro-Silverberg Fund for the Advancement of Translational Research at the Center for Clinical and Translational Science of the Rockefeller University, and the Research Grant Program from the Immune Deficiency Foundation. D. Lee. was supported by FRMfellowship (FDM202006011282). C.S.M was supported by an Early-Mid Career Research Fellowship from the Department of Health of the New South Wales Government of Australia. S.G.T was supported by an NHMRC Leadership 3 Investigator Grant (1176665) and NHMRC grant (1113904). M.O. was supported by the David Rockefeller Graduate Program, the Funai Foundation for Information Technology, the Honjo International Scholarship Foundation, and the New York Hideyo Noguchi Memorial Society. This work was supported by grants from ANRS (ECTZ118797), Sidaction (20-2-AEQ-12822-2), and FRM (EQU202103012774) to N. Manel, and H.I. was supported by fellowships from Institut Curie, Seneca Foundation (20941/PD/18), and ANRS (ECTZ171453). A.N.S. was supported in part by the European Union’s Horizon 2020 research and innovation program (789645 Marie Sklodowska-Curie grant). Y.-H.C. is supported by an A∗STAR International Fellowship. J. Bohlen is an EMBO postdoctoral fellow. We thank the NIH Tetramer Core Facility (NTCF) for providing the 5-OP-RU-loaded MR1 tetramer, which was developed jointly with Dr. James McCluskey, Dr. Jamie Rossjohn, and Dr. David Fairlie., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-16-CE17-0005,GENMSMD,Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme(2016), ANR-20-CO11-0001,AABIFNCOV,Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19.(2020), ANR-21-COVR-0039,GenMIS-C,Recherche des Déficits immunitaires innées monogéniques prédisposant au syndrome inflammatoire multisystémique chez l'enfant.(2021), ANR-19-CE15-0012,SUNLIVE,Variabilité structurale et fonctionnelle des lipides complexes chez les mycobactéries : de l'assemblage de la paroi à la physiopathologie et virulence(2019), ANR-22-CE92-0008,MAFMACRO,Genetic predisposition and the role of myeloid cells in the susceptibility to mycobacterial infection(2022), European Project: 824110,H2020-INFRAIA-2018-1,EASI-Genomics(2019), and TÜREL, ÖZDEN

Subjects
inborn errors of immunity, Temel Bilimler, [SDV]Life Sciences [q-bio], interferon-stimulated gene, Life Sciences, Molecular Biology and Genetics, Genel Biyokimya, Genetik ve Moleküler Biyoloji, IRF1, General Biochemistry, Genetics and Molecular Biology, Mycobacterium, macrophages, interferon-γ, Yaşam Bilimleri, viruses, Cytogenetic, Natural Sciences, Moleküler Biyoloji ve Genetik, Sitogenetik
Abstract

Inborn errors of human IFN-γ-dependent macrophagic immunity underlie mycobacterial diseases, whereas inborn errors of IFN-α/β-dependent intrinsic immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria and related intramacrophagic pathogens. These children have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2, which is life-threatening in individuals with impaired IFN-α/β immunity. In leukocytes or fibroblasts stimulated in vitro, IRF1-dependent responses to IFN-γ are, both quantitatively and qualitatively, much stronger than those to IFN-α/β. Moreover, IRF1-deficient mononuclear phagocytes do not control mycobacteria and related pathogens normally when stimulated with IFN-γ. By contrast, IFN-α/β-dependent intrinsic immunity to nine viruses, including SARS-CoV-2, is almost normal in IRF1-deficient fibroblasts. Human IRF1 is essential for IFN-γ-dependent macrophagic immunity to mycobacteria, but largely redundant for IFN-α/β-dependent antiviral immunity.

Published
2023

47. Clonal hematopoiesis driven by chromosome 1q/MDM4 trisomy defines a canonical route toward leukemia in Fanconi anemia

Author

Marie Sebert, Stéphanie Gachet, Thierry Leblanc, Alix Rousseau, Olivier Bluteau, Rathana Kim, Raouf Ben Abdelali, Flore Sicre de Fontbrune, Loïc Maillard, Carèle Fedronie, Valentine Murigneux, Léa Bellenger, Naira Naouar, Samuel Quentin, Lucie Hernandez, Nadia Vasquez, Mélanie Da Costa, Pedro H. Prata, Lise Larcher, Marie de Tersant, Matthieu Duchmann, Anna Raimbault, Franck Trimoreau, Odile Fenneteau, Wendy Cuccuini, Nathalie Gachard, Nathalie Auger, Giulia Tueur, Maud Blanluet, Claude Gazin, Michèle Souyri, Francina Langa Vives, Aaron Mendez-Bermudez, Hélène Lapillonne, Etienne Lengline, Emmanuel Raffoux, Pierre Fenaux, Lionel Adès, Edouard Forcade, Charlotte Jubert, Carine Domenech, Marion Strullu, Bénédicte Bruno, Nimrod Buchbinder, Caroline Thomas, Arnaud Petit, Guy Leverger, Gérard Michel, Marina Cavazzana, Eliane Gluckman, Yves Bertrand, Nicolas Boissel, André Baruchel, Jean-Hugues Dalle, Emmanuelle Clappier, Eric Gilson, Ludovic Deriano, Sylvie Chevret, François Sigaux, Gérard Socié, Dominique Stoppa-Lyonnet, Hugues de Thé, Christophe Antoniewski, Dominique Bluteau, Régis Peffault de Latour, Jean Soulier, Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), AP-HP Hôpital universitaire Robert-Debré [Paris], Recherche clinique appliquée à l'hématologie (URP_3518), Intégrité du génome, immunité et cancer - Genome integrity, Immunity and Cancer, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Limoges, Institut Gustave Roussy (IGR), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Hématopoïèse normale et pathologique : émergence, environnement et recherche translationnelle [Paris] ((UMR_S1131 / U1131)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre d'Ingénierie génétique murine - Mouse Genetics Engineering Center (CIGM), Institut Pasteur [Paris] (IP), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), CHU Nice [Cimiez], Hôpital Cimiez [Nice] (CHU), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpitaux universitaires Est parisien [AP-HP], CHU Bordeaux [Bordeaux], Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [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), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Rouen, Normandie Université (NU), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre d'études et de recherche sur les services de santé et la qualité de vie (CEReSS), Aix Marseille Université (AMU), Hôpital de la Timone [CHU - APHM] (TIMONE), CIC NECKER BT (CIC 1416), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Collège de France (CdF (institution)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL), This study received support from the European Research Council (ERC) Consolidator Grant to J.S. (CEVAL-311660), the FP7 Eurofancolen program (HEALTH-F5-2012-305421), the ANR program PACRI (Projet alliance parisienne des instituts de recherche en cancérologie), the CONECT-AML (Collaborative Network for Children and Teenagers with Acute Myeloid Leukemia) program supported by a grant from the Institut National du Cancer (INCa), Fondation ARC, Ligue nationale contre le cancer, and Laurette Fugain (INCa-ARC-LIGUE_11905) to J.S. and C.A., and the Association Française pour la Maladie de Fanconi (AFMF) grants 'Histoire naturelle de la maladie de Fanconi' to R.P.L. and J.S., 'Modélisation de la transformation leucémique dans la maladie de Fanconi' to D.B., and 'Cribles fonctionnels à haut débit de gènes modificateurs de la maladie de Fanconi' to C.G. M.S. was supported by the AVIESAN-INCa Program 'Formation à la Recherche Translationnelle,' and A.R. by a grant from the Fondation ARC. The work in E.G.’s lab is supported by Fondation ARC and ANR Telochrom. The work in L.D.’s lab is supported by INCa (PLBIO16-181) and ERC (310917)., ANR-11-PHUC-0002,PACRI,Alliance Parisienne des Instituts de Recherche en Cancérologie(2011), European Project: 311660,EC:FP7:ERC,ERC-2012-StG_20111109,CEVAL(2013), and European Project: 305421,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,EUROFANCOLEN(2013)

Subjects
MDM4, Fanconi anemia, precision medicine, [SDV]Life Sciences [q-bio], Genetics, leukemia, clonal hematopoiesis, Molecular Medicine, Cell Biology, TP53, mutational signature, genomic instability, BRCA2
Abstract

International audience; Fanconi anemia (FA) patients experience chromosome instability, yielding hematopoietic stem/progenitor cell (HSPC) exhaustion and predisposition to poor-prognosis myeloid leukemia. Based on a longitudinal cohort of 335 patients, we performed clinical, genomic, and functional studies in 62 patients with clonal evolution. We found a unique pattern of somatic structural variants and mutations that shares features of BRCA-related cancers, the FA-hallmark being unbalanced, microhomology-mediated translocations driving copy-number alterations. Half the patients developed chromosome 1q gain, driving clonal hematopoiesis through MDM4 trisomy downmodulating p53 signaling later followed by secondary acute myeloid lukemia genomic alterations. Functionally, MDM4 triplication conferred greater fitness to murine and human primary FA HSPCs, rescued inflammation-mediated bone marrow failure, and drove clonal dominance in FA mouse models, while targeting MDM4 impaired leukemia cells in vitro and in vivo. Our results identify a linear route toward secondary leukemogenesis whereby early MDM4-driven downregulation of basal p53 activation plays a pivotal role, opening monitoring and therapeutic prospects.

Published
2023

48. A novel cancer risk prediction score for the natural course of FA patients with biallelic BRCA2/FANCD1 mutations

Author

Ivana Radulovic, Michael M Schündeln, Lisa Müller, Johannes Ptok, Ellen Honisch, Dieter Niederacher, Constanze Wiek, Kathrin Scheckenbach, Thierry Leblanc, Lise Larcher, Jean Soulier, Dirk Reinhardt, Heiner Schaal, Paul R Andreassen, and Helmut Hanenberg

Subjects
Genetics, Medizin, General Medicine, Molecular Biology, Genetics (clinical)
Abstract

Biallelic germline mutations in BRCA2 occur in the Fanconi anemia (FA)-D1 subtype of the rare pediatric disorder, FA, characterized clinically by severe congenital abnormalities and a very high propensity to develop malignancies early in life. Clinical and genetic data from 96 FA-D1 patients with biallelic BRCA2 mutations were collected and used to develop a new cancer risk prediction score system based on the specific mutations in BRCA2. This score takes into account the location of frameshift/stop and missense mutations relative to exon 11 of BRCA2, which encodes the major sites for interaction with the RAD51 recombinase, and uses the MaxEnt and HBond splicing scores to analyze potential splice site perturbations. Among 75 FA-D1 patients with ascertained BRCA2 mutations, 66 patients developed 102 malignancies, ranging from one to three independent tumors per individual. The median age at the clinical presentation of peripheral embryonal tumors was 1.0, at the onset of hematologic malignancies 1.8 and at the manifestation of CNS tumors 2.7 years, respectively. Patients who received treatment lived longer than those without. Using our novel scoring system, we could distinguish three distinct cancer risk groups among FA-D1 patients: in the first, patients developed their initial malignancy at a median age of 1.3 years (n = 36, 95% CI = 0.9–1.8), in the second group at 2.3 years (n = 17, 95% CI = 1.4–4.4) and in the third group at 23.0 years (n = 22, 95% CI = 4.3—n/a). Therefore, this scoring system allows, for the first time, to predict the cancer manifestation of FA-D1 patients simply based on the type and position of the mutations in BRCA2.

Published
2023

49. The Clinical Picture of the ERCC6L2 Disease - from Bone Marrow Failure to Acute Leukemia

Author

Marja Hakkarainen, Ilse Kaaja, Suvi P. M. Douglas, Thomas J Vulliamy, Inderjeet Dokal, Jean Soulier, Lise Larcher, Régis Peffault de Latour, Thierry M Leblanc, Flore Sicre de Fontbrune, Timo Siitonen, Olli Lohi, Eva Hellström-Lindberg, Gisela Barbany, Bianca Tesi, Akiko Shimamura, Fabian Beier, Sharon Rosalie Jackson, Amir Kuperman, Tzipora C. Falik Zaccai, Hannah Tamary, Cristina Mecucci, Ilaria Capolsini, Kirsi Jahnukainen, Urpu Salmenniemi, Riitta Niinimäki, Teppo Varilo, Outi Kilpivaara, and Ulla Wartiovaara-Kautto

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Abstract

Biallelic germline ERCC6L2 variants strongly predispose to bone marrow failure (BMF) and myeloid malignancies characterized by somatic TP53-mutated clones and erythroid predominance. We present a series of 52 subjects (35 families) with ERCC6L2 biallelic germline variants collected retrospectively in 11 centers globally, including follow-up of 1165 person-years. At initial investigations, 32 individuals were diagnosed with BMF and 15 with a hematological malignancy (HM). Subjects presented with 19 different variants across ERCC6L2, and we identified a founder mutation c.1424delT in the Finnish patients. The median age of subjects at baseline was 18 years (range 2-65). Changes in complete blood count (CBC) were mild despite severe bone marrow hypoplasia and somatic TP53 mutations, with no significant difference between subjects with or without (HM). Signs of a progressive disease were increasing TP53 variant allele frequency, dysplasia in megakaryocytes and/or erythroid lineage, and erythroid predominance in bone marrow morphology. The median age at onset of HM was 37.0 years (95% CI: 31.5-42.5; range 12-65). Overall survival (OS) at 3 years was 95% (95% CI: 85-100) and 19% (95% CI: 0-39) for patients with BMF and HM, respectively. Patients with myelodysplastic syndrome or acute myeloid leukemia with mutated TP53 undergoing hematopoietic stem cell transplantation had a poor outcome: 3-year OS is 28% (95% CI: 0-61). Our results demonstrate the importance of early recognition and active surveillance of patients with biallelic germline ERCC6L2 variants.

Published
2023

50. Molecular International Prognostic Scoring System (IPSS-M) in Myelodysplastic Syndromes Arising from Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria

Author

Carmelo Gurnari, Pedro H. Prata, Luiz Fernando Bazzo Catto, Arda Durmaz, Lise Larcher, Marie Sebert, Vincent Allain, Tariq Kewan, Simona Pagliuca, Andre Luiz Pinto, Mariana C. B. Inacio, Lucie Hernandez, Nathalie Dhedin, Sophie Caillat-Zucman, Emmanuelle Clappier, Flore Sicre de Fontbrune, Maria Teresa Voso, Valeria Visconte, Régis Peffault de Latour, Jean Soulier, Gérard Socié, Rodrigo T. Calado, and Jaroslaw P. Maciejewski

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022

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