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1. TPM3-ALK expression induces changes in cytoskeleton organisation and confers higher metastatic capacities than other ALK fusion proteins

Author

Christian Touriol, Laurence Lamant, Georges Delsol, Corinne Hieblot, and Florence Armstrong

Subjects
Cancer Research, Lung Neoplasms, Blotting, Western, Mice, Nude, Tropomyosin, Biology, Transfection, Mice, hemic and lymphatic diseases, Animals, Humans, Anaplastic lymphoma kinase, Anaplastic Lymphoma Kinase, Cytoskeleton, Actin, Receptor Protein-Tyrosine Kinases, Protein-Tyrosine Kinases, Actin cytoskeleton, Immunohistochemistry, Fusion protein, Oncology, Cell culture, NIH 3T3 Cells, Cancer research, Lymphoma, Large B-Cell, Diffuse
Abstract

Translocations of the anaplastic lymphoma kinase (ALK) gene result in the production of a number of oncogenic ALK fusion proteins implicated in tumour development. We have previously shown that X-ALK fusion proteins have differential effects on the proliferation, transformation, and invasion properties of NIH3T3 cells in vitro. In the present study, we have investigated the metastatic potential of various X-ALK expressing cell lines using an experimental lung metastasis assay. We have shown that TPM3-ALK expression bestows higher metastatic capacities than other X-ALK fusion proteins and in addition, that TPM3-ALK fusion protein expression specifically induces changes in cell morphology and cytoskeleton organisation. Co-immunoprecipitation studies demonstrate a specific interaction between TPM3-ALK and endogenous tropomyosin. Together the specific actions of TPM3-ALK on the cytoskeleton organisation offer an interesting hypothesis with respect to the higher cell motility and metastatic potential of this fusion protein.

Published
2007
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2. Interleukin‐18 produced by bone marrow‐derived stromal cells supports T ‐cell acute leukaemia progression

Author

Paola Ballerini, Florence Armstrong, Françoise Pflumio, André Baruchel, Frederic Baleydier, Véronique Baud, Sandrine Poglio, Julia Gross, Thierry Leblanc, Julien Calvo, Diana Passaro, Judith Landman-Parker, Caroline Deswarte, Florent Dumont, Ching-Lien Wu, Xavier Cahu, Jacques Ghysdael, Corinne Besnard-Guerin, Bastien Gerby, Benjamin Uzan, Françoise Porteu, Institut de Radiobiologie Cellulaire et Moléculaire (IRCM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université, Jet Propulsion Laboratory (JPL), California Institute of Technology (CALTECH)-NASA, Service d'hématologie pédiatrique, Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), 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-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Chimie Moléculaire (SCM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), AGeing and IMagery (AGIM), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Mobile Network Performance Group, Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Inorganic Chemistry Laboratory [Oxford], University of Oxford, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service d'hématologie et immunologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Oncologie Médicale [Centre hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Bos, Mireille, Rheinisch-Westfälische Technische Hochschule Aachen (RWTH), University of Oxford [Oxford], Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École Pratique des Hautes Études (EPHE), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie Clinique, Centre hospitalier universitaire de Nantes (CHU Nantes), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], NASA-California Institute of Technology (CALTECH), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre de Recherche en Cancérologie de Lyon (CRCL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), CEA Direction des Sciences du Vivant (CEA/DSV), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service de Chimie Moléculaire ( SCM ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ), AGeing and IMagery ( AGIM ), Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -École pratique des hautes études ( EPHE ) -Centre National de la Recherche Scientifique ( CNRS ), RWTH Aachen University [Aachen], Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service d'hématologie-immunologie-oncologie pédiatrique, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Centre de Recherche en Cancérologie de Lyon ( 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 Lyon Sud [CHU - HCL] ( CHLS ), and Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL )

Subjects
MAPK/ERK pathway, Stromal cell, MAP Kinase Signaling System, T-Lymphocytes, medicine.medical_treatment, T cell, [SDV]Life Sciences [q-bio], Bone Marrow Cells, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Cell Line, Mice, 03 medical and health sciences, 0302 clinical medicine, Mice, Inbred NOD, Cell Line, Tumor, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Gene Silencing, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Research Articles, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, 030304 developmental biology, stromal cells, 0303 health sciences, Gene Expression Regulation, Leukemic, Cell growth, Interleukin-18, T-ALL Subject Categories Cancer, Cytokine, medicine.anatomical_structure, Cell culture, inflammation, 030220 oncology & carcinogenesis, Immunology, Cancer research, Molecular Medicine, Interleukin 18, Bone marrow, T-ALL, IL-18, Haematology
Abstract

International audience; Development of novel therapies is critical for T-cell acute leukae-mia (T-ALL). Here, we investigated the effect of inhibiting the MAPK/MEK/ERK pathway on T-ALL cell growth. Unexpectedly, MEK inhibitors (MEKi) enhanced growth of 70% of human T-ALL cell samples cultured on stromal cells independently of NOTCH activa-tion and maintained their ability to propagate in vivo. Similar results were obtained when T-ALL cells were cultured with ERK1/ 2-knockdown stromal cells or with conditioned medium from MEKi-treated stromal cells. Microarray analysis identified interleu-kin 18 (IL-18) as transcriptionally up-regulated in MEKi-treated MS5 cells. Recombinant IL-18 promoted T-ALL growth in vitro, whereas the loss of function of IL-18 receptor in T-ALL blast cells decreased blast proliferation in vitro and in NSG mice. The NFKB pathway that is downstream to IL-18R was activated by IL-18 in blast cells. IL-18 circulating levels were increased in T-ALL-xeno-grafted mice and also in T-ALL patients in comparison with controls. This study uncovers a novel role of the pro-inflammatory cytokine IL-18 and outlines the microenvironment involvement in human T-ALL development.

Published
2014
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3. Expression of CD34 and CD7 on human T-cell acute lymphoblastic leukemia discriminates functionally heterogeneous cell populations

Author

Françoise Pflumio, J Calvo, E Clappier, Florence Armstrong, Paola Ballerini, Thierry Leblanc, S Poglio, Judith Landman-Parker, N Boissel, Jean Soulier, Bastien Gerby, Caroline Deswarte, Paul-Henri Romeo, André Baruchel, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Hémato-oncologie [CHU Saint-Louis], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Jet Propulsion Laboratory (JPL), NASA-California Institute of Technology (CALTECH), Unité d'Hémato-Immunologie pédiatrique [Hôpital Robert Debré, Paris], Service d'Immuno-hématologie pédiatrique [Hôpital Robert Debré, Paris], Hôpital Robert Debré-Hôpital Robert Debré, Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Laboratoire d'électronique, optoélectronique et microsystèmes (LEOM), École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
Cancer Research, T cell, [SDV]Life Sciences [q-bio], CD34, Antigens, CD34, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antigens, CD7, Biology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Dexamethasone, 03 medical and health sciences, Mice, 0302 clinical medicine, Mice, Inbred NOD, hemic and lymphatic diseases, medicine, Animals, Humans, Peripheral blood cell, Progenitor cell, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Cell Proliferation, 0303 health sciences, Acute leukemia, Receptors, Notch, Hematology, medicine.disease, Molecular biology, 3. Good health, Hematopoiesis, Leukemia, Haematopoiesis, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Immunology, Neoplastic Stem Cells, Stem cell, Signal Transduction
Abstract

Leukemia-initiating/repopulating cells (LICs), also named leukemic stem cells, are responsible for propagating human acute leukemia. Although they have been characterized in various leukemias, their role in T-cell acute lymphoblastic leukemia (T-ALL) is unclear. To identify and characterize LICs in T-ALL (T-LIC), we fractionated peripheral blood cell populations from patient samples by flow cytometry into three cell fractions by using two markers: CD34 (a marker of immature cells and LICs) and CD7 (a marker of early T-cell differentiation). We tested these populations in both in vitro culture assays and in vivo for growth and leukemia development in immune-deficient mice. We found LIC activity in CD7(+) cells only as CD34(+)CD7(-) cells contained normal human progenitors and hematopoietic stem cells that differentiated into T, B lymphoid and myeloid cells. In contrast, CD34(+)CD7(+) cells were enriched in LICs, when compared with CD34(-)CD7(+) cells. These CD34(+)CD7(+) cells also proliferated more upon NOTCH activation than CD34(-)CD7(+) cells and were sensitive to dexamethasone and NOTCH inhibitors. These data show that CD34 and CD7 expression in human T-ALL samples help in discriminating heterogeneous cell populations endowed with different LIC activity, proliferation capacity and responses to drugs.

Published
2011
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4. NKX3.1 is a direct TAL1 target gene that mediates proliferation of TAL1-expressing human T cell acute lymphoblastic leukemia

Author

Nathalie Gault, Federica Ferri, Sophie Kusy, Nicolas Goardon, Paul-Henri Romeo, Bastien Gerby, Françoise Pflumio, André Baruchel, Florence Armstrong, Jean-Michel Cayuela, Delphine Gérard, Paola Ballerini, Laboratoire de biologie et de génétique du cancer [Caen] (UNICANCER - Centre François Baclesse), Centre Régional de Lutte contre le Cancer François Baclesse (CRLC François Baclesse ), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Département de biostatistiques [AP-HP Hôpital Bichat, Paris], Unité de recherche clinique [AP-HP Hôpital Bichat, Paris], AP-HP - Hôpital Bichat - Claude Bernard [Paris]-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Université de Lorraine (UL), Inorganic Chemistry Laboratory [Oxford], University of Oxford [Oxford], Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Service d'hématologie pédiatrique, Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), CEA Direction des Sciences du Vivant (CEA/DSV), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), University of Oxford, CHU Trousseau [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Male, Tumor suppressor gene, T cell, [SDV]Life Sciences [q-bio], Immunology, Notch signaling pathway, [SDV.CAN]Life Sciences [q-bio]/Cancer, GATA3 Transcription Factor, Biology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, urologic and male genital diseases, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, Proto-Oncogene Proteins, Metalloproteins, Basic Helix-Loop-Helix Transcription Factors, Gene Knockdown Techniques, medicine, Animals, Humans, Immunology and Allergy, Genes, Tumor Suppressor, Transcription factor, T-Cell Acute Lymphocytic Leukemia Protein 1, ComputingMilieux_MISCELLANEOUS, Adaptor Proteins, Signal Transducing, Cell Proliferation, 030304 developmental biology, Homeodomain Proteins, Regulation of gene expression, 0303 health sciences, Gene knockdown, urogenital system, Stem Cells, Prostate, LIM Domain Proteins, DNA-Binding Proteins, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Neoplasm Transplantation, Protein Binding, Transcription Factors, TAL1
Abstract

TAL1 (also known as SCL) is expressed in >40% of human T cell acute lymphoblastic leukemias (T-ALLs). TAL1 encodes a basic helix-loop-helix transcription factor that can interfere with the transcriptional activity of E2A and HEB during T cell leukemogenesis; however, the oncogenic pathways directly activated by TAL1 are not characterized. In this study, we show that, in human TAL1–expressing T-ALL cell lines, TAL1 directly activates NKX3.1, a tumor suppressor gene required for prostate stem cell maintenance. In human T-ALL cell lines, NKX3.1 gene activation is mediated by a TAL1–LMO–Ldb1 complex that is recruited by GATA-3 bound to an NKX3.1 gene promoter regulatory sequence. TAL1-induced NKX3.1 activation is associated with suppression of HP1-α (heterochromatin protein 1 α) binding and opening of chromatin on the NKX3.1 gene promoter. NKX3.1 is necessary for T-ALL proliferation, can partially restore proliferation in TAL1 knockdown cells, and directly regulates miR-17-92. In primary human TAL1-expressing leukemic cells, the NKX3.1 gene is expressed independently of the Notch pathway, and its inactivation impairs proliferation. Finally, TAL1 or NKX3.1 knockdown abrogates the ability of human T-ALL cells to efficiently induce leukemia development in mice. These results suggest that tumor suppressor or oncogenic activity of NKX3.1 depends on tissue expression.

Published
2010
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5. Optimized gene transfer into human primary leukemic T cell with NOD-SCID/leukemia-initiating cell activity

Author

S Amselem, Judith Landman-Parker, Irwin D. Bernstein, Hervé Dombret, P B de la Grange, Florence Armstrong, André Baruchel, Paola Ballerini, Els Verhoeyen, Thierry Leblanc, Françoise Pflumio, H Medyouf, N Boissel, J Calvo, François-Loïc Cosset, Bastien Gerby, Laboratoire de Recherche sur les Cellules Souches Hématopoiétiques et Leucémiques (LSHL), Université Paris Diderot - Paris 7 (UPD7)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Hémato-oncologie [CHU Saint-Louis], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Jet Propulsion Laboratory (JPL), NASA-California Institute of Technology (CALTECH), Unité d'Hémato-Immunologie pédiatrique [Hôpital Robert Debré, Paris], Service d'Immuno-hématologie pédiatrique [Hôpital Robert Debré, Paris], Hôpital Robert Debré-Hôpital Robert Debré, Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (Equipe EVIR), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), California Institute of Technology (CALTECH)-NASA, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Cancer Research, T cell, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, Nod, Mice, SCID, Biology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, 03 medical and health sciences, Transduction (genetics), Mice, 0302 clinical medicine, Viral Envelope Proteins, Mice, Inbred NOD, Transduction, Genetic, medicine, Animals, Humans, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Cell Proliferation, 0303 health sciences, Membrane Glycoproteins, Cell growth, Interleukin-7, Genetic transfer, Lentivirus, Gene Transfer Techniques, Biological activity, Hematology, T lymphocyte, medicine.disease, Virology, 3. Good health, Leukemia, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Cancer research
Abstract

Optimized gene transfer into human primary leukemic T cell with NOD-SCID/leukemia-initiating cell activity

Published
2009
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6. NOTCH is a key regulator of human T-cell acute leukemia initiating cell activity

Author

Judith Landman-Parker, Philippe Brunet de la Grange, Bastien Gerby, Paul-Henri Romeo, Nicolas Boissel, Michaela Fontenay, Françoise Pflumio, Julien Calvo, André Baruchel, Florence Armstrong, Paola Ballerini, Hervé Dombret, Marie-Christine Rouyez, Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Service d'hématologie-oncologie adultes, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service d'hématologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), Université Pierre et Marie Curie - Paris 6 (UPMC), Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Trousseau [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Cellular immunity, Stromal cell, [SDV]Life Sciences [q-bio], Immunology, Notch signaling pathway, Regulator, Cell Culture Techniques, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Communication, Mice, SCID, Biology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Biochemistry, 03 medical and health sciences, Mice, 0302 clinical medicine, Mice, Inbred NOD, Calcium-binding protein, Precursor cell, Tumor Cells, Cultured, Animals, Humans, Receptor, Notch1, Receptor, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Cell growth, Calcium-Binding Proteins, Genes, T-Cell Receptor gamma, Membrane Proteins, Cell Biology, Hematology, Coculture Techniques, Cell biology, 030220 oncology & carcinogenesis, Intercellular Signaling Peptides and Proteins, Amyloid Precursor Protein Secretases, Stromal Cells, Oligopeptides, Neoplasm Transplantation, Signal Transduction
Abstract

Understanding the pathways that regulate the human T-cell acute lymphoblastic leukemia (T-ALL) initiating cells (T-LiC) activity has been hampered by the lack of biologic assays in which this human disease can be studied. Here we show that coculture of primary human T-ALL with a mouse stromal cell line expressing the NOTCH ligand delta-like-1 (DL1) reproducibly allowed maintenance of T-LiC and long-term growth of blast cells. Human T-ALL mutated or not on the NOTCH receptor required sustained activation of the NOTCH pathway via receptor/ligand interaction for growth and T-LiC activity. On the reverse, inhibition of the NOTCH pathway during primary cultures abolished in vitro cell growth and in vivo T-LiC activity. Altogether, these results demonstrate the major role of the NOTCH pathway activation in human T-ALL development and in the maintenance of leukemia-initiating cells.

Published
2009
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7. A 'liaison dangereuse' between AUF1/hnRNPD and the oncogenic tyrosine kinase NPM-ALK

Author

Bernard Monsarrat, Severine Ollier, Henri Dupont, Florence Armstrong, Mohamad Fawal, Dominique Morello, Georges Delsol, Christian Touriol, Bernard Payrastre, Groupe d'analyse et de théorie économique ( GATE ), Université Lumière - Lyon 2 ( UL2 ) -Ecole Normale Supérieure Lettres et Sciences Humaines-Centre National de la Recherche Scientifique ( CNRS ), Centre de REcherches sur les Stratégies Economiques - UFC ( CRESE ), Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), Institut de pharmacologie et de biologie structurale ( IPBS ), Université Paul Sabatier - Toulouse 3 ( UPS ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Physiopathologie Toulouse Purpan, Université Paul Sabatier - Toulouse 3 ( UPS ) -IFR30-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Groupe d'analyse et de théorie économique (GATE), Université Lumière - Lyon 2 (UL2)-Ecole Normale Supérieure Lettres et Sciences Humaines (ENS LSH)-Centre National de la Recherche Scientifique (CNRS), Centre de REcherches sur les Stratégies Economiques (EA 3190) (CRESE), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de REcherches sur les Stratégies Economiques (UR 3190) (CRESE), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), and 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)

Subjects
MESH: Cell Death, MESH : Molecular Sequence Data, MESH : RNA, Messenger, Oncogene Proteins, Fusion, MESH : NIH 3T3 Cells, Genes, myc, MESH: Amino Acid Sequence, MESH : Models, Biological, MESH : Oncogene Proteins, Fusion, Biochemistry, Mice, MESH : Phosphorylation, 0302 clinical medicine, hemic and lymphatic diseases, Anaplastic lymphoma kinase, MESH: Animals, MESH: Lymphoma, Large-Cell, RNA, Neoplasm, Heterogeneous-Nuclear Ribonucleoprotein D, Phosphorylation, Anaplastic large-cell lymphoma, 0303 health sciences, Cell Death, integumentary system, Kinase, MESH : Amino Acid Sequence, Hematology, Protein-Tyrosine Kinases, Cell biology, MESH : Genes, myc, 030220 oncology & carcinogenesis, Lymphoma, Large B-Cell, Diffuse, Signal transduction, MESH : Transfection, Tyrosine kinase, Immunology, Molecular Sequence Data, MESH : Cyclins, Biology, MESH : Heterogeneous-Nuclear Ribonucleoprotein D, Transfection, Models, Biological, MESH: Protein-Tyrosine Kinases, 03 medical and health sciences, Cyclins, MESH : Mice, medicine, MESH : Protein-Tyrosine Kinases, Animals, Humans, Heterogeneous Nuclear Ribonucleoprotein D0, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, RNA, Messenger, MESH: Mice, MESH : Lymphoma, Large-Cell, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Genes, myc, 030304 developmental biology, MESH: RNA, Messenger, MESH: Heterogeneous-Nuclear Ribonucleoprotein D, MESH: Molecular Sequence Data, MESH: Humans, MESH: Phosphorylation, Cell growth, MESH: Transfection, MESH : Humans, MESH: Models, Biological, Cell Biology, medicine.disease, MESH: RNA, Neoplasm, MESH: Cyclins, Fusion protein, MESH : RNA, Neoplasm, MESH : Cell Death, NIH 3T3 Cells, MESH : Animals, MESH: NIH 3T3 Cells, MESH: Oncogene Proteins, Fusion
Abstract

Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is a chimeric protein expressed in a subset of cases of anaplastic large cell lymphoma (ALCL) for which constitutive expression represents a key oncogenic event. The ALK signaling pathway is complex and probably involves functional redundancy between various signaling substrates of ALK. Despite numerous studies on signaling mediators, the molecular mechanisms contributing to the distinct oncogenic features of NPM-ALK remain incompletely understood. The search for additional interacting partners of NPM-ALK led to the discovery of AUF1/hnRNPD, a protein implicated in AU-rich element (ARE)-directed mRNA decay. AUF1 was immunoprecipitated with ALK both in ALCL-derived cells and in NIH3T3 cells stably expressing NPM-ALK or other X-ALK fusion proteins. AUF1 and NPM-ALK were found concentrated in the same cytoplasmic foci, whose formation required NPM-ALK tyrosine kinase activity. AUF1 was phosphorylated by ALK in vitro and was hyperphosphorylated in NPM-ALK-expressing cells. Its hyperphosphorylation was correlated with increased stability of several AUF1 target mRNAs encoding key regulators of cell proliferation and with increased cell survival after transcriptional arrest. Thus, AUF1 could function in a novel pathway mediating the oncogenic effects of NPM-ALK. Our data establish an important link between oncogenic kinases and mRNA turnover, which could constitute a critical aspect of tumorigenesis.

Published
2006
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8. Low SCL/TAL1 expression reveals its major role in adult hematopoietic myeloid progenitors and stem cells

Author

Paul-Henri Romeo, Florence Armstrong, Philippe Brunet de la Grange, Françoise Pflumio, Veronique Duval, Marie-Christine Rouyez, and Nicolas Goardon

Subjects
Adult, Myeloid, Oncogene Proteins, Fusion, T-Lymphocytes, Immunology, CD34, Cell Culture Techniques, Stem cell factor, Biology, Biochemistry, Colony-Forming Units Assay, Mice, Mice, Inbred NOD, medicine, Animals, Humans, Progenitor cell, Severe combined immunodeficiency, B-Lymphocytes, Stem Cells, Intracellular Signaling Peptides and Proteins, Infant, Cell Biology, Hematology, medicine.disease, Hematopoietic Stem Cells, Cell biology, Hematopoiesis, Transplantation, Haematopoiesis, medicine.anatomical_structure, Gene Expression Regulation, Stem cell
Abstract

Stem cell leukemia/T cell acute leukemia 1 (SCL/TAL1) plays a key role in the development of murine primitive hematopoiesis but its functions in adult definitive hematopoiesis are still unclear. Using lentiviral delivery of TAL1-directed shRNA in human hematopoietic cells, we show that decreased expression of TAL1 induced major disorders at different levels of adult hematopoietic cell development. Erythroid and myeloid cell production in cultures was dramatically decreased in TAL1-directed shRNA-expressing cells, whereas lymphoid B-cell development was normal. These results confirm the role of TAL1 in the erythroid compartment and show TLA1's implication in the function of myeloid committed progenitors. Moreover, long-term cultures and transplantation of TAL1-directed shRNA-expressing CD34+ cells into irradiated nonobese diabetic–severe combined immunodeficient (NOD-SCID) mice led to dramatically low levels of human cells of all lineages including the B-lymphoid lineage, strongly suggesting that TAL1 has a role in the early commitment of hematopoietic stem cells (HSCs) in humans. Cultures and transplantation experiments performed with mouse Sca1+ cells gave identical results. Altogether, these observations definitively show that TAL1 participates in the regulation of hematopoiesis from HSCs to myeloid progenitors, and pinpoint TAL1 as a master protein of human and murine adult hematopoiesis.

Published
2006

9. Acute T-Cell Leukemias Remain Dependent On Notch Signaling Despite PTEN and INK4A/ARF Loss

Author

Françoise Pflumio, Andrew P. Weng, Qing Liu, Samuel Gusscott, Hind Medyouf, Kirk R. Schultz, Larry H. Matherly, M J You, Xiuhua Gao, Florence Armstrong, and Amanda Larson Gedman

Subjects
Tumor suppressor gene, T cell, Immunology, Notch signaling pathway, Mice, SCID, Signal transduction inhibitor, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Biochemistry, Mice, Mice, Inbred NOD, Transduction, Genetic, medicine, Animals, Tensin, PTEN, RNA, Messenger, Enzyme Inhibitors, Receptor, Notch1, Cyclin-Dependent Kinase Inhibitor p16, Bone Marrow Transplantation, Mice, Knockout, Leukemia, Experimental, Lymphoid Neoplasia, biology, Reverse Transcriptase Polymerase Chain Reaction, PTEN Phosphohydrolase, Cell Biology, Hematology, Flow Cytometry, medicine.disease, Leukemia, Retroviridae, medicine.anatomical_structure, Cancer research, biology.protein, Amyloid Precursor Protein Secretases, Signal transduction, Interleukin Receptor Common gamma Subunit, Signal Transduction
Abstract

Abstract 8 T-cell acute lymphoblastic leukemia (T-ALL) is a malignancy of immature T cell progenitors in which activating mutations of NOTCH1 occur in over 50% of cases and loss-of-function mutations in FBW7, which degrades activated NOTCH1, occur in 8-16% of cases. We and others have characterized c-MYC as a critical downstream transcriptional target of Notch signaling in this context, and loss of FBW7 also contributes here as intact FBW7 marks c-MYC protein for proteosomal degradation. Inhibition of Notch signaling in T-ALL cells by various means including small molecule gamma-secretase inhibitors (GSI) causes cell cycle/growth arrest and in some cases apoptosis, providing rationale for NOTCH1 as a therapeutic target. The tumor suppressor PTEN is also mutated or lost in up to 20% of T-ALL cases. PTEN activity converts PIP3 to PIP2, and thus loss of PTEN potentiates PI3K signaling. It was observed among human T-ALL cell lines that PTEN loss correlated with resistance to Notch inhibition with GSI, leading to the idea that constitutive PI3K/AKT signaling relieves T-ALL cells of their “addiction” to oncogenic Notch signaling. Since GSI and other NOTCH1 signaling inhibitors are presently under investigation as targeted therapeutic agents for T-ALL and other cancers including breast, brain, colorectal, pancreatic, and melanoma, this idea that PTEN loss could confer resistance to NOTCH1 inhibition raises concern that patients with PTEN-negative (or presumably PIK3CA-mutated) diseases may fail Notch inhibitor therapy. As the studies linking GSI-resistance/Notch-independence to PTEN loss were limited to established cell lines, we sought to address this issue using a well established and genetically defined mouse retroviral transduction/bone marrow transplantation model. Briefly, we generated primary murine T-cell acute leukemias using mutated NOTCH1 retroviruses on both wild-type and PTEN-null backgrounds and tested these tumors for response to GSI. Unexpectedly, we observed these primary murine leukemias to undergo growth arrest and cell size reduction with GSI treatment on both wild-type and PTEN-null backgrounds. We even observed wild-type background tumors which had lost PTEN spontaneously after either serial transplantation or extended culture in vitro to remain sensitive to GSI. Given that most cases of human T-ALL have also lost expression of p16INK4A/p14ARF tumor suppressors either by deletion or silencing, and since p16INK4A/p14ARF are critical regulators at the G1/S cell cycle checkpoint, we also generated primary murine tumors on a Pten, Ink4a/Arf double-null background. Even when both PTEN and Ink4a/Arf were deleted, we still observed the murine tumors to remain sensitive to GSI. To confirm these findings were not unique to murine tumors, we examined a panel of 13 primary human T-ALL cases including 7 PTEN-positive cases (6 of which were NOTCH1 mutated) and 6 PTEN-negative cases (4 of which were NOTCH1 mutated). We found 11 of these 13 cases to be GSI sensitive (6 PTEN-positive, 5 PTEN-negative) as illustrated by decreased proliferation and reduction in cell size. We found only 2 cases to be GSI resistant, including 1 PTEN-positive and 1 PTEN-negative. Our panel contained only one case with FBW7 mutation; this case was PTEN-positive and GSI-sensitive. Thus, in contrast to previous studies with established cell lines, we find in this study using primary human T-ALL samples and genetically defined primary murine leukemias that PTEN loss indeed does not confer resistance to Notch inhibition. Of note, other groups have postulated a role for FBW7 mutation in conferring resistance to Notch inhibition; however, we encountered only 2 GSI-resistant cases in our panel of primary human samples, neither of which was FBW7 mutated. In generating the murine Notch leukemias, we also had the opportunity to compare disease penetrance/latency and clonality among the various genetic backgrounds. We noted that PTEN loss was associated with accelerated disease onset and multiclonal tumors as compared to wild-type, whereas INK4A/ARF loss alone had no such effect. These findings suggest NOTCH1 activation and PTEN loss may collaborate in leukemia induction; however, technical caveats related to potentially enhanced retroviral transduction efficiency of PTEN-null bone marrow progenitors limit this conclusion, and thus more definitive experiments to address this issue are needed. Disclosures: No relevant conflicts of interest to declare.

Published
2009
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