RRC ID 69708
Author Koya J, Kataoka K, Sato T, Bando M, Kato Y, Tsuruta-Kishino T, Kobayashi H, Narukawa K, Miyoshi H, Shirahige K, Kurokawa M.
Title DNMT3A R882 mutants interact with polycomb proteins to block haematopoietic stem and leukaemic cell differentiation.
Journal Nat Commun
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.
Volume 7
Pages 10924
Published 2016-3-24
DOI 10.1038/ncomms10924
PII ncomms10924
PMID 27010239
PMC PMC4820786
MeSH Animals Bone Marrow Cells / drug effects Bone Marrow Cells / metabolism Cell Differentiation / drug effects Cell Differentiation / genetics* Cell Transformation, Neoplastic / drug effects Cell Transformation, Neoplastic / pathology Cells, Cultured DNA (Cytosine-5-)-Methyltransferases / genetics* DNA Methylation / genetics DNA Methyltransferase 3A Down-Regulation / drug effects Gene Silencing / drug effects Hematopoietic Stem Cells / drug effects Hematopoietic Stem Cells / metabolism Hematopoietic Stem Cells / pathology* Leukemia, Myeloid, Acute / enzymology Leukemia, Myeloid, Acute / genetics Leukemia, Myeloid, Acute / pathology* Mice, Inbred C57BL Mutant Proteins / metabolism Mutation / genetics* Polycomb Repressive Complex 1 / metabolism Polycomb-Group Proteins / metabolism* Protein Binding / drug effects Tretinoin / pharmacology
IF 12.121
Human and Animal Cells KG-1(RCB1166)