| RRC ID |
69708
|
| 著者 |
Koya J, Kataoka K, Sato T, Bando M, Kato Y, Tsuruta-Kishino T, Kobayashi H, Narukawa K, Miyoshi H, Shirahige K, Kurokawa M.
|
| タイトル |
DNMT3A R882 mutants interact with polycomb proteins to block haematopoietic stem and leukaemic cell differentiation.
|
| ジャーナル |
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.
|
| 巻・号 |
7
|
| ページ |
10924
|
| 公開日 |
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
|
| リソース情報 |
| ヒト・動物細胞 |
KG-1(RCB1166) |
