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1. B-cell tumor development in Tet2-deficient mice

Author

Enguerran Mouly, Hussein Ghamlouch, Veronique Della-Valle, Laurianne Scourzic, Cyril Quivoron, Damien Roos-Weil, Patrycja Pawlikowska, Véronique Saada, M'Boyba K. Diop, Cécile K. Lopez, Michaela Fontenay, Philippe Dessen, Ivo P. Touw, Thomas Mercher, Said Aoufouchi, and Olivier A. Bernard

Subjects
Specialties of internal medicine, RC581-951
Abstract

Abstract: The TET2 gene encodes an α-ketoglutarate–dependent dioxygenase able to oxidize 5-methylcytosine into 5-hydroxymethylcytosine, which is a step toward active DNA demethylation. TET2 is frequently mutated in myeloid malignancies but also in B- and T-cell malignancies. TET2 somatic mutations are also identified in healthy elderly individuals with clonal hematopoiesis. Tet2-deficient mouse models showed widespread hematological differentiation abnormalities, including myeloid, T-cell, and B-cell malignancies. We show here that, similar to what is observed with constitutive Tet2-deficient mice, B-cell–specific Tet2 knockout leads to abnormalities in the B1-cell subset and a development of B-cell malignancies after long latency. Aging Tet2-deficient mice accumulate clonal CD19+ B220low immunoglobulin M+ B-cell populations with transplantable ability showing similarities to human chronic lymphocytic leukemia, including CD5 expression and sensitivity to ibrutinib-mediated B-cell receptor (BCR) signaling inhibition. Exome sequencing of Tet2−/− malignant B cells reveals C-to-T and G-to-A mutations that lie within single-stranded DNA–specific activation-induced deaminase (AID)/APOBEC (apolipoprotein B messenger RNA editing enzyme, catalytic polypeptide-like) cytidine deaminases targeted motif, as confirmed by the lack of a B-cell tumor in compound Tet2-Aicda–deficient mice. Finally, we show that Tet2 deficiency accelerates and exacerbates T-cell leukemia/lymphoma 1A–induced leukemogenesis. Together, our data establish that Tet2 deficiency predisposes to mature B-cell malignancies, which development might be attributed in part to AID-mediated accumulating mutations and BCR-mediated signaling.

Published
2018
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2. A prospective study of bone marrow hematopoietic and mesenchymal stem cells in type 1 Gaucher disease patients.

Author

Séverine Lecourt, Enguerran Mouly, Delphine Freida, Audrey Cras, Raphaël Ceccaldi, Djazia Heraoui, Christine Chomienne, Jean-Pierre Marolleau, Bertrand Arnulf, Raphael Porcher, Catherine Caillaud, Valérie Vanneaux, Nadia Belmatoug, and Jérôme Larghero

Subjects
Medicine, Science
Abstract

Gaucher disease (GD) is an autosomal recessive disorder characterized by lysosomal glucocerebrosidase (GBA) deficiency leading to hematological and skeletal manifestations. Mechanisms underlying these symptoms have not yet been elucidated. In vivo, bone marrow (BM) mesenchymal stem cells (MSCs) have important role in the regulation of bone mass and in the support of hematopoiesis, thus representing potential candidate that could contribute to the disease. GBA deficiency may also directly impair hematopoietic stem/progenitors cells (HSPCs) intrinsic function and induce hematological defect. In order to evaluate the role of BM stem cells in GD pathophysiology, we prospectively analyzed BM-MSCs and HSPCs properties in a series of 10 patients with type 1 GD. GBA activity was decreased in all tested cell subtypes. GD-MSCs had an impaired growth potential, morphological and cell cycle abnormalities, decreased capacities to differentiate into osteoblasts. Moreover, GD-MSCs secreted soluble factors that stimulated osteoclasts resorbing activities. In vitro and in vivo primitive and mature hematopoiesis were similar between patients and controls. However, GD-MSCs had a lower hematopoietic supportive capacity than those from healthy donors. These data suggest that BM microenvironment is altered in GD and that MSCs are key components of the manifestations observed in GD.

Published
2013
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3. The human immunodeficiency virus-1 protease inhibitor nelfinavir impairs proteasome activity and inhibits the proliferation of multiple myeloma cells in vitro and in vivo

Author

Camille Bono, Lionel Karlin, Stephanie Harel, Enguerran Mouly, Sylvaine Labaume, Lionel Galicier, Sébastien Apcher, Hélène Sauvageon, Jean-Paul Fermand, Jean-Christophe Bories, and Bertrand Arnulf

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

Background Multiple myeloma is characterized by the accumulation of tumor plasma cells in the bone marrow. Despite therapeutic improvements brought by proteasome inhibitors such as bortezomib, myeloma remains an incurable disease. In a variety of human cancers, human immunodeficiency virus protease inhibitors (e.g. nelfinavir) effectively inhibit tumor progression, but their impact on myeloma is unknown. We assessed the in vitro and in vivo effects of nelfinavir on multiple myeloma.Design and Methods The effects of nelfinavir (1–10 μM) on proteasome activity, proliferation and viability of myeloma cell lines and plasma cells from patients were assessed by measuring PERK, AKT, STAT3 and ERK1/2 phosphorylation and CHOP expression with immunoblotting or flow cytometry. The in vivo effect was assessed in NOD/SCID mice injected with luciferase expressing human myeloma cell lines and treated with nelfinavir at a dose of 75 mg/kg/day. Tumor progression was evaluated using a bioluminescent system.Results Nelfinavir inhibited 26S chymotrypsin-like proteasome activity, impaired proliferation and triggered apoptosis of the myeloma cell lines and fresh plasma cells. It activated the pro-apoptotic unfolded protein response pathway by inducing PERK phosphorylation and CHOP expression. Cell death triggered by nelfinavir treatment correlated with decreased phosphorylation of AKT, STAT3 and ERK1/2. Nelfinavir enhanced the anti-proliferative activity of bortezomib, dexamethasone and histone deacetylase inhibitors and delayed tumor growth in a myeloma mouse model.Conclusions These results suggest that nelfinavir, used at a pharmacological dosage, alone or in combination, may be useful in the treatment of myeloma. Our data provide a preclinical basis for clinical trials using nelfinavir in patients with myeloma.

Published
2012
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4. Nfkbie-deficiency leads to increased susceptibility to develop B-cell lymphoproliferative disorders in aged mice

Author

Veronique, Della-Valle, Damien, Roos-Weil, Laurianne, Scourzic, Enguerran, Mouly, Zakia, Aid, Walaa, Darwiche, Yann, Lecluse, Frederik, Damm, Sylvie, Mémet, Thomas, Mercher, Said, Aoufouchi, Florence, Nguyen-Khac, Olivier A, Bernard, Hussein, Ghamlouch, Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Université de Picardie Jules Verne (UPJV), CHU Amiens-Picardie, Plateforme imagerie et cytométrie (PFIC), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Humboldt University Of Berlin, Berlin Institute of Health (BIH), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Intégrité du génome et cancers (IGC), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie clinique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Humboldt-Universität zu Berlin, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie Biologique [CHU Pitié-Salpêtrière], and Gestionnaire, Hal Sorbonne Université

Subjects
Chronic lymphocytic leukaemia, B cells, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, B-cell lymphoma, [SDV]Life Sciences [q-bio], Oncogenes, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Leukemia, Lymphocytic, Chronic, B-Cell, lcsh:RC254-282, Article, [SDV] Life Sciences [q-bio], Mice, Proto-Oncogene Proteins, Animals, I-kappa B Proteins, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Aberrant NF-κB activation is a hallmark of most B-cell malignancies. Recurrent inactivating somatic mutations in the NFKBIE gene, which encodes IκBε, an inhibitor of NF-κB-inducible activity, are reported in several B-cell malignancies with highest frequencies in chronic lymphocytic leukemia and primary mediastinal B-cell lymphoma, and account for a fraction of NF-κB pathway activation. The impact of NFKBIE deficiency on B-cell development and function remains, however, largely unknown. Here, we show that Nfkbie-deficient mice exhibit an amplification of marginal zone B cells and an expansion of B1 B-cell subsets. In germinal center (GC)-dependent immune response, Nfkbie deficiency triggers expansion of GC B-cells through increasing cell proliferation in a B-cell autonomous manner. We also show that Nfkbie deficiency results in hyperproliferation of a B1 B-cell subset and leads to increased NF-κB activation in these cells upon Toll-like receptor stimulation. Nfkbie deficiency cooperates with mutant MYD88 signaling and enhances B-cell proliferation in vitro. In aged mice, Nfkbie absence drives the development of an oligoclonal indolent B-cell lymphoproliferative disorders, resembling monoclonal B-cell lymphocytosis. Collectively, these findings shed light on an essential role of IκBε in finely tuning B-cell development and function.

Published
2020

5. DNMT3AR882H mutant and Tet2 inactivation cooperate in the deregulation of DNA methylation control to induce lymphoid malignancies in mice

Author

Cécile K. Lopez, Kristian Helin, Elena Mylonas, Michaela Fontenay, Enguerran Mouly, Françoise Pflumio, P. Gaulard, Marianne Terndrup Pedersen, M'Boyba Diop, Michael Weber, Laurianne Scourzic, Lucile Couronné, Nathalie Droin, O. Bernard, Julien Calvo, Patrice Dubreuil, Ambre Bender, Philippe Dessen, N Martin, V Della Valle, Sylvain Guibert, Thomas Mercher, Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), Hématopoïèse normale et pathologique ( U1170 Inserm ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Gustave Roussy ( IGR ), Génétique des tumeurs ( U985 ), Institut Gustave Roussy ( IGR ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Norwegian Defence Intelligence School [Oslo] ( NDUC ), Centre de recherche en économie et management ( CREM ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ), Centro de Aplicaciones de Tecnologías de Avanzada ( CENATAV ), CENATAV, Laboratoire Ligérien de Linguistique ( LLL ), Bibliothèque nationale de France ( BnF ) -Université d'Orléans ( UO ) -Université de Tours-Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), The Unilever Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge [UK] ( CAM ), Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Images et Modèles, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé ( CREATIS ), Université Jean Monnet [Saint-Étienne] ( UJM ) -Hospices Civils de Lyon ( HCL ) -Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Jean Monnet [Saint-Étienne] ( UJM ) -Hospices Civils de Lyon ( HCL ) -Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), and Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )

Subjects
0301 basic medicine, Cancer Research, Myeloid, Cellular differentiation, Notch signaling pathway, Biology, Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire, medicine.disease_cause, Article, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, DNA Methyltransferase 3A, Dioxygenases, 03 medical and health sciences, Mice, Proto-Oncogene Proteins, medicine, Animals, Genes, Tumor Suppressor, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, DNA (Cytosine-5-)-Methyltransferases, Mutation, Receptors, Notch, Myeloid leukemia, Cell Differentiation, Hematology, DNA Methylation, Lymphoproliferative Disorders, Transplantation, Gene expression profiling, DNA-Binding Proteins, 030104 developmental biology, medicine.anatomical_structure, Oncology, embryonic structures, DNA methylation, Immunology, Cancer research
Abstract

International audience; TEN-ELEVEN-TRANSLOCATION-2 (TET2) and DNA-METHYLTRANSFERASE-3A (DNMT3A), both encoding proteins involved in regulating DNA methylation, are mutated in hematological malignancies affecting both myeloid and lymphoid lineages. We previously reported an association of TET2 and DNMT3A mutations in progenitors of patients with angioimmunoblastic T-cell lymphomas (AITL). Here, we report on the cooperative effect of Tet2 inactivation and DNMT3A mutation affecting arginine 882 (DNMT3A(R882H)) using a murine bone marrow transplantation assay. Five out of eighteen primary recipients developed hematological malignancies with one mouse developing an AITL-like disease, two mice presenting acute myeloid leukemia (AML)-like and two others T-cell acute lymphoblastic leukemia (T-ALL)-like diseases within 6 months following transplantation. Serial transplantations of DNMT3A(R882H) Tet2(-/-) progenitors led to a differentiation bias toward the T-cell compartment, eventually leading to AITL-like disease in 9/12 serially transplanted recipients. Expression profiling suggested that DNMT3A(R882H) Tet2(-/-) T-ALLs resemble those of NOTCH1 mutant. Methylation analysis of DNMT3A(R882H) Tet2(-/-) T-ALLs showed a global increase in DNA methylation affecting tumor suppressor genes and local hypomethylation affecting genes involved in the Notch pathway. Our data confirm the transformation potential of DNMT3A(R882H) Tet2(-/-) progenitors and represent the first cooperative model in mice involving Tet2 inactivation driving lymphoid malignancies.

Published
2016

6. A prospective study of bone marrow hematopoietic and mesenchymal stem cells in type 1 Gaucher disease patients

Author

Djazia Heraoui, Christine Chomienne, Audrey Cras, Nadia Belmatoug, Valérie Vanneaux, Catherine Caillaud, Enguerran Mouly, Séverine Lecourt, Raphael Ceccaldi, Bertrand Arnulf, Jean-Pierre Marolleau, Raphaël Porcher, Jérôme Larghero, and Delphine Freida

Subjects
Male, Cellular differentiation, Osteoclasts, lcsh:Medicine, Mice, Autosomal Recessive, Bone Marrow, Prospective Studies, Stem Cell Niche, lcsh:Science, Multidisciplinary, Hematology, Stem Cells, Cell Differentiation, Middle Aged, Adult Stem Cells, Haematopoiesis, Gaucher's disease, medicine.anatomical_structure, Cellular Microenvironment, Glucosylceramidase, Medicine, Female, Stem cell, Research Article, Adult, medicine.medical_specialty, Bone Marrow Cells, Biology, Internal medicine, Genetics, medicine, Animals, Humans, Progenitor cell, Aged, Cell Proliferation, Gaucher Disease, Osteoblasts, Mesenchymal stem cell, lcsh:R, Mesenchymal Stem Cells, Human Genetics, Hematopoietic Stem Cells, medicine.disease, Case-Control Studies, Immune System, Immunology, Clinical Immunology, lcsh:Q, Bone marrow, Developmental Biology
Abstract

Gaucher disease (GD) is an autosomal recessive disorder characterized by lysosomal glucocerebrosidase (GBA) deficiency leading to hematological and skeletal manifestations. Mechanisms underlying these symptoms have not yet been elucidated. In vivo, bone marrow (BM) mesenchymal stem cells (MSCs) have important role in the regulation of bone mass and in the support of hematopoiesis, thus representing potential candidate that could contribute to the disease. GBA deficiency may also directly impair hematopoietic stem/progenitors cells (HSPCs) intrinsic function and induce hematological defect. In order to evaluate the role of BM stem cells in GD pathophysiology, we prospectively analyzed BM-MSCs and HSPCs properties in a series of 10 patients with type 1 GD. GBA activity was decreased in all tested cell subtypes. GD-MSCs had an impaired growth potential, morphological and cell cycle abnormalities, decreased capacities to differentiate into osteoblasts. Moreover, GD-MSCs secreted soluble factors that stimulated osteoclasts resorbing activities. In vitro and in vivo primitive and mature hematopoiesis were similar between patients and controls. However, GD-MSCs had a lower hematopoietic supportive capacity than those from healthy donors. These data suggest that BM microenvironment is altered in GD and that MSCs are key components of the manifestations observed in GD.

Published
2013

7. TET proteins and the control of cytosine demethylation in cancer

Author

Enguerran Mouly, Laurianne Scourzic, and Olivier Bernard

Subjects
Genetics, Cellular differentiation, Review, Methylation, Biology, DNA methyltransferase, chemistry.chemical_compound, Isocitrate dehydrogenase, chemistry, DNA methylation, Cancer research, Molecular Medicine, Genetics(clinical), Gene, Molecular Biology, Genetics (clinical), Cytosine, Demethylation
Abstract

The discovery that ten-eleven translocation (TET) proteins are α-ketoglutarate-dependent dioxygenases involved in the conversion of 5-methylcytosines (5-mC) to 5-hydroxymethylcytosine (5-hmC), 5-formylcytosine and 5-carboxycytosine has revealed new pathways in the cytosine methylation and demethylation process. The description of inactivating mutations in TET2 suggests that cellular transformation is in part caused by the deregulation of this 5-mC conversion. The direct and indirect deregulation of methylation control through mutations in DNA methyltransferase and isocitrate dehydrogenase (IDH) genes, respectively, along with the importance of cytosine methylation in the control of normal and malignant cellular differentiation have provided a conceptual framework for understanding the early steps in cancer development. Here, we review recent advances in our understanding of the cytosine methylation cycle and its implication in cellular transformation, with an emphasis on TET enzymes and 5-hmC. Ongoing clinical trials targeting the activity of mutated IDH enzymes provide a proof of principle that DNA methylation is targetable, and will trigger further therapeutic applications aimed at controlling both early and late stages of cancer development.

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