RRC ID 35761
Author 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.
Title Polycomb-dependent epigenetic landscape in adult T-cell leukemia.
Journal 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.
Volume 127(14)
Pages 1790-802
Published 2016-4-7
DOI 10.1182/blood-2015-08-662593
PII blood-2015-08-662593
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 15.132
Times Cited 8
WOS Category HEMATOLOGY
Resource
DNA material CSII-EF-MCS-IRES2-Venus (RDB04384)