DNMT3A R882突变体与多梳蛋白相互作用，以阻断造血干细胞和白血病细胞的分化。
DNMT3A R882 mutants interact with polycomb proteins to block haematopoietic stem and leukaemic cell differentiation.
作者信息
Koya Junji, Kataoka Keisuke, Sato Tomohiko, Bando Masashige, Kato Yuki, Tsuruta-Kishino Takako, Kobayashi Hiroshi, Narukawa Kensuke, Miyoshi Hiroyuki, Shirahige Katsuhiko, Kurokawa Mineo
机构信息
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.
出版信息
Nat Commun. 2016 Mar 24;7:10924. doi: 10.1038/ncomms10924.
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.
尽管DNMT3A突变对急性髓系白血病具有临床影响，但关于这种突变如何在体内引发白血病发生的分子机制在很大程度上尚不清楚。在此我们表明，在小鼠移植实验中，移植了转导有DNMT3A突变体的细胞的受体表现出异常的造血干细胞（HSC）积累。在转导有DNMT3A突变体的干/祖细胞中，与分化相关的基因被下调，而其启动子相关的CpG岛的甲基化状态没有伴随变化，这代表了突变的DNMT3A的一种不依赖DNA甲基化的作用。DNMT3A R882H还与HOXA9协同促进体外单核细胞转化。在分子层面，DNMT3A突变体与多梳抑制复合物1（PRC1）相互作用，导致转录沉默，揭示了DNMT3A突变的一种不依赖DNA甲基化的作用。抑制PRC1会损害异常的HSC积累和单核细胞转化。从我们的数据可以看出，DNMT3A突变体可通过PRC1阻断HSC和白血病细胞的分化。这种相互作用在DNMT3A突变的白血病中可能是可靶向作用的。
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