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; Mineo Kurokawa

doi:10.1038/ncomms10924

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, Mineo Kurokawa

Research output: Contribution to journal › Article › peer-review

53 Citations (Scopus)

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.

Original language	English
Article number	10924
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms10924
Publication status	Published - 2016 Mar 24
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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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.",

author = "Junji Koya and Keisuke Kataoka and Tomohiko Sato and Masashige Bando and Yuki Kato and Takako Tsuruta-Kishino and Hiroshi Kobayashi and Kensuke Narukawa and Hiroyuki Miyoshi and Katsuhiko Shirahige and Mineo Kurokawa",

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AU - Koya, Junji

AU - Kataoka, Keisuke

AU - Sato, Tomohiko

AU - Bando, Masashige

AU - Kato, Yuki

AU - Tsuruta-Kishino, Takako

AU - Kobayashi, Hiroshi

AU - Narukawa, Kensuke

AU - Miyoshi, Hiroyuki

AU - Shirahige, Katsuhiko

AU - Kurokawa, Mineo

PY - 2016/3/24

Y1 - 2016/3/24

N2 - 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.

AB - 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.

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

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