Format

Send to

Choose Destination
Nat Commun. 2016 Mar 24;7:10924. doi: 10.1038/ncomms10924.

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

Author information

1
Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, bunkyo-ku, Tokyo 113-8655, Japan.
2
Department of Transfusion Medicine, The University of Tokyo Hospital, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
3
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.
4
Subteam for Manipulation of Cell Fate, RIKEN BioResource Center, 3-1-1, Koyadai, Tsukuba-shi, Ibaraki 305-0074, Japan.
5
Department of Cell Therapy and Transplantation, The University of Tokyo Hospital, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.

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.

PMID:
27010239
PMCID:
PMC4820786
DOI:
10.1038/ncomms10924
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center