title: DNMT3A R882 mutants interact with polycomb proteins to block haematopoietic stem and leukaemic cell differentiation.
abstract: Despite the clinical impact of DNMT3A mutation on acute myeloid leukaemia, the molecular mechanisms regarding how this mutation causes leukaemogenesis in vivo are largely unknown. Here we show that, in murine transplantation experiments, recipients transplanted with DNMT3A mutant-transduced cells exhibit aberrant haematopoietic stem cell (HSC) accumulation. Differentiation-associated genes are downregulated without accompanying changes in methylation status of their promoter-associated CpG islands in DNMT3A mutant-transduced stem/progenitor cells, representing a DNA methylation-independent role of mutated DNMT3A. DNMT3A R882H also promotes monoblastic transformation in vitro in combination with HOXA9. Molecularly, the DNMT3A mutant interacts with polycomb repressive complex 1 (PRC1), causing transcriptional silencing, revealing a DNA methylation-independent role of DNMT3A mutation. Suppression of PRC1 impairs aberrant HSC accumulation and monoblastic transformation. From our data, it is shown that DNMT3A mutants can block the differentiation of HSCs and leukaemic cells via PRC1. This interaction could be targetable in DNMT3A-mutated leukaemias.
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Koya
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Keisuke
authors.identifier: http://orcid.org/0000-0002-8263-9902
authors.initials: K
authors.lastname: Kataoka
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, bunkyo-ku, Tokyo 113-8655, Japan.|Department of Transfusion Medicine, The University of Tokyo Hospital, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Sato
authors.affiliation: Laboratory of Genome Structure and Function, Research Center for Epigenetic Disease, Institute for Molecular and Cellular Biosciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Masashige
authors.initials: M
authors.lastname: Bando
authors.affiliation: Laboratory of Genome Structure and Function, Research Center for Epigenetic Disease, Institute for Molecular and Cellular Biosciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kato
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Tsuruta-Kishino
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Narukawa
authors.affiliation: Subteam for Manipulation of Cell Fate, RIKEN BioResource Center, 3-1-1, Koyadai, Tsukuba-shi, Ibaraki 305-0074, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyoshi
authors.affiliation: Laboratory of Genome Structure and Function, Research Center for Epigenetic Disease, Institute for Molecular and Cellular Biosciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Shirahige
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, bunkyo-ku, Tokyo 113-8655, Japan.|Department of Cell Therapy and Transplantation, The University of Tokyo Hospital, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Mineo
authors.initials: M
authors.lastname: Kurokawa
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology; D002478:Cells, Cultured; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D015536:Down-Regulation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D008810:Mice, Inbred C57BL; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism; D063146:Polycomb-Group Proteins / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D050505:Mutant Proteins; D063146:Polycomb-Group Proteins; D014212:Tretinoin; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D063150:Polycomb Repressive Complex 1; C489841:RNF2 protein, human