| RRC ID |
35761
|
| 著者 |
Fujikawa D, Nakagawa S, Hori M, Kurokawa N, Soejima A, Nakano K, Yamochi T, Nakashima M, Kobayashi S, Tanaka Y, Iwanaga M, Utsunomiya A, Uchimaru K, Yamagishi M, Watanabe T.
|
| タイトル |
Polycomb-dependent epigenetic landscape in adult T-cell leukemia.
|
| ジャーナル |
Blood
|
| Abstract |
Adult T-cell leukemia-lymphoma (ATL) shows global gene expression alterations that confer cellular characteristics and unfavorable prognosis. However, molecular mechanisms of the sustained expression changes are largely unknown, because there is no study addressing the relationship between landscapes of the gene expression and epigenetic modifications. Here, we analyzed ATL epigenome and integrated it with transcriptome from primary ATL cells and those from corresponding normal CD4(+)T cells to decipher ATL-specific "epigenetic code" that was critical for cell identity. We found that polycomb-repressive complex 2 (PRC2)-mediated trimethylation at histone H3Lys27 (H3K27me3) was significantly and frequently reprogrammed at half of genes in ATL cells. A large proportion of the abnormal gene downregulation was detected at the early stage of disease progression and was explained by H3K27me3 accumulation. The global H3K27me3 alterations involved ATL-specific gene expression changes that included several tumor suppressors, transcription factors, epigenetic modifiers, miRNAs, and developmental genes, suggesting diverse outcomes by the PRC2-dependent hierarchical regulation. Interestingly, a key enzyme, EZH2, was sensitive to promiscuous signaling network including the NF-κB pathway and was functionally affected by human T-cell leukemia virus type I (HTLV-1) Tax. The Tax-dependent immortalized cells showed H3K27me3 reprogramming that was significantly similar to that of ATL cells. Of note, a majority of the epigenetic silencing has occurred in leukemic cells from indolent ATL and also in HTLV-1-infected T cells from asymptomatic HTLV-1 carriers. Because pharmacologic inhibition of EZH2 reversed epigenetic disruption and selectively eliminated leukemic and HTLV-1-infected cells, targeting the epigenetic elements will hold great promise in treatment and prevention of the onset of ATL and HTLV-1-related diseases.
|
| 巻・号 |
127(14)
|
| ページ |
1790-802
|
| 公開日 |
2016-4-7
|
| DOI |
10.1182/blood-2015-08-662593
|
| PII |
S0006-4971(20)30280-9
|
| PMID |
26773042
|
| MeSH |
Adult
Cell Line, Transformed
Cell Line, Tumor
Enhancer of Zeste Homolog 2 Protein
Epigenesis, Genetic*
Female
Gene Expression Regulation, Leukemic*
Gene Products, tax / genetics
Gene Products, tax / metabolism
Histones / genetics
Histones / metabolism
Human T-lymphotropic virus 1 / genetics
Human T-lymphotropic virus 1 / metabolism
Humans
Leukemia-Lymphoma, Adult T-Cell / genetics
Leukemia-Lymphoma, Adult T-Cell / metabolism*
Leukemia-Lymphoma, Adult T-Cell / pathology
Male
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism*
Polycomb Repressive Complex 2 / genetics
Polycomb Repressive Complex 2 / metabolism*
|
| IF |
17.794
|
| 引用数 |
51
|
|
WOS 分野
|
HEMATOLOGY
|
| リソース情報 |
| 遺伝子材料 |
CSII-EF-MCS-IRES2-Venus （RDB04384） |
