title: DNMT3A(R882H) mutant and Tet2 inactivation cooperate in the deregulation of DNA methylation control to induce lymphoid malignancies in mice.
abstract: 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.
authors.affiliation: INSERM U1170, Villejuif, France.|Equipe labellisée Ligue Nationale Contre le Cancer, Paris, France.|Université Paris-Sud, Orsay, France.|Gustave Roussy, Villejuif, France.
authors.forename: L
authors.initials: L
authors.lastname: Scourzic
authors.affiliation: INSERM U1170, Villejuif, France.|Equipe labellisée Ligue Nationale Contre le Cancer, Paris, France.|Université Paris-Sud, Orsay, France.|Gustave Roussy, Villejuif, France.
authors.forename: L
authors.initials: L
authors.lastname: Couronné
authors.affiliation: Biotech Research and Innovation Centre (BRIC), Copenhagen, Denmark.|Centre for Epigenetics, Copenhagen, Denmark.
authors.forename: M T
authors.initials: MT
authors.lastname: Pedersen
authors.affiliation: INSERM U1170, Villejuif, France.|Equipe labellisée Ligue Nationale Contre le Cancer, Paris, France.|Université Paris-Sud, Orsay, France.|Gustave Roussy, Villejuif, France.
authors.forename: V
authors.initials: V
authors.lastname: Della Valle
authors.affiliation: INSERM U1170, Villejuif, France.|Equipe labellisée Ligue Nationale Contre le Cancer, Paris, France.|Université Paris-Sud, Orsay, France.|Gustave Roussy, Villejuif, France.
authors.forename: M
authors.initials: M
authors.lastname: Diop
authors.affiliation: INSERM U1170, Villejuif, France.|Equipe labellisée Ligue Nationale Contre le Cancer, Paris, France.|Université Paris-Sud, Orsay, France.|Gustave Roussy, Villejuif, France.
authors.forename: E
authors.initials: E
authors.lastname: Mylonas
authors.affiliation: Equipe labellisée Ligue Nationale Contre le Cancer, Paris, France.|Université Paris-Sud, Orsay, France.|INSERM U967, Fontenay-aux-Roses, France.|CEA, DSV-IRCM-SCSR-LSHL, Fontenay-aux-Roses, France.
authors.forename: J
authors.initials: J
authors.lastname: Calvo
authors.affiliation: INSERM U1170, Villejuif, France.|Equipe labellisée Ligue Nationale Contre le Cancer, Paris, France.|Gustave Roussy, Villejuif, France.|Université Paris-Sud, Orsay, France.
authors.forename: E
authors.identifier: 0000-0003-2151-7511
authors.initials: E
authors.lastname: Mouly
authors.affiliation: INSERM U1170, Villejuif, France.|Université Paris-Sud, Orsay, France.|Gustave Roussy, Villejuif, France.
authors.forename: C K
authors.initials: CK
authors.lastname: Lopez
authors.affiliation: INSERM U955, Créteil, France.|Université Paris-Est, Créteil, France.
authors.forename: N
authors.initials: N
authors.lastname: Martin
authors.affiliation: Département d'Immuno-Hématologie, Hôpital Cochin, Paris, France.|INSERM U1016, Centre National de la Recherche Scientifique (CNRS) UMR 8104, Institut Cochin, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Fontenay
authors.affiliation: CNRS, Université de Strasbourg, UMR7242, Illkirch, France.
authors.forename: A
authors.initials: A
authors.lastname: Bender
authors.affiliation: CNRS, Université de Strasbourg, UMR7242, Illkirch, France.
authors.forename: S
authors.initials: S
authors.lastname: Guibert
authors.affiliation: INSERM U1068, CRCM, CNRS, Université Aix-Marseille, Marseille, France.|Institut Paoli-Calmettes, Marseille, France.
authors.forename: P
authors.initials: P
authors.lastname: Dubreuil
authors.affiliation: INSERM U1170, Villejuif, France.|Equipe labellisée Ligue Nationale Contre le Cancer, Paris, France.|Université Paris-Sud, Orsay, France.|Gustave Roussy, Villejuif, France.
authors.forename: P
authors.initials: P
authors.lastname: Dessen
authors.affiliation: INSERM U1170, Villejuif, France.|Equipe labellisée Ligue Nationale Contre le Cancer, Paris, France.|Université Paris-Sud, Orsay, France.|Gustave Roussy, Villejuif, France.
authors.forename: N
authors.initials: N
authors.lastname: Droin
authors.affiliation: Equipe labellisée Ligue Nationale Contre le Cancer, Paris, France.|Université Paris-Sud, Orsay, France.|INSERM U967, Fontenay-aux-Roses, France.|CEA, DSV-IRCM-SCSR-LSHL, Fontenay-aux-Roses, France.
authors.forename: F
authors.initials: F
authors.lastname: Pflumio
authors.affiliation: CNRS, Université de Strasbourg, UMR7242, Illkirch, France.
authors.forename: M
authors.initials: M
authors.lastname: Weber
authors.affiliation: INSERM U955, Créteil, France.|Université Paris-Est, Créteil, France.|Département de Pathologie, Hôpital Henri Mondor, Créteil, France.
authors.forename: P
authors.initials: P
authors.lastname: Gaulard
authors.affiliation: Biotech Research and Innovation Centre (BRIC), Copenhagen, Denmark.|Centre for Epigenetics, Copenhagen, Denmark.|The Danish Stem Cell Center, Copenhagen, Denmark.
authors.forename: K
authors.identifier: 0000-0003-1975-6097
authors.initials: K
authors.lastname: Helin
authors.affiliation: INSERM U1170, Villejuif, France.|Université Paris-Sud, Orsay, France.|Gustave Roussy, Villejuif, France.
authors.forename: T
authors.initials: T
authors.lastname: Mercher
authors.affiliation: INSERM U1170, Villejuif, France.|Equipe labellisée Ligue Nationale Contre le Cancer, Paris, France.|Université Paris-Sud, Orsay, France.|Gustave Roussy, Villejuif, France.
authors.forename: O A
authors.initials: OA
authors.lastname: Bernard
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins / Q000235:genetics*; D049308:Dioxygenases; D016147:Genes, Tumor Suppressor; D008232:Lymphoproliferative Disorders / Q000209:etiology / Q000235:genetics*; D051379:Mice; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051880:Receptors, Notch / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C000715535:Dnmt3a protein, mouse; D011518:Proto-Oncogene Proteins; D051880:Receptors, Notch; D049308:Dioxygenases; C551914:Tet2 protein, mouse; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A