DNMT3A R882 mutants interact with polycomb proteins to block haematopoietic stem and leukaemic cell differentiation

Junji Koya, Keisuke Kataoka, Tomohiko Sato, Masashige Bando, Yuki Kato, Takako Tsuruta-Kishino, Hiroshi Kobayashi, Kensuke Narukawa, Hiroyuki Miyoshi, Katsuhiko Shirahige and Mineo Kurokawa ()
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Junji Koya: Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, bunkyo-ku
Keisuke Kataoka: Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, bunkyo-ku
Tomohiko Sato: Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, bunkyo-ku
Masashige Bando: 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
Yuki Kato: 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
Takako Tsuruta-Kishino: Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, bunkyo-ku
Hiroshi Kobayashi: Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, bunkyo-ku
Kensuke Narukawa: Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, bunkyo-ku
Hiroyuki Miyoshi: Subteam for Manipulation of Cell Fate, RIKEN BioResource Center, 3-1-1, Koyadai
Katsuhiko Shirahige: 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
Mineo Kurokawa: Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, bunkyo-ku

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10924

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