Polycomb-dependent epigenetic landscape in adult T-cell leukemia.

Adult T-cell leuκemia-lymphoma (ATL) shows global gene expression alterations that confer cellular characteristics and unfavorable prognosis. However, molecular mechanisms of the sustained expression changes are largely unκnown, because there is no study addressing the relationship between landscapes of the gene expression and epigenetic modifications.Here, we analyzedATL epigenomeand integrated itwith transcriptome from primary ATL cells and those from corresponding normal CD41+ cells to decipher ATL-specific "epigenetic code" that was critical for cell identity. We found that polycombrepressive 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 κey enzyme, EZH2, was sensitive to promiscuous signaling networκ including the NF-κB pathway and was functionally affected by human T-cell leuκemia 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 leuκemic 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 leuκemic 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. (Blood. 2016;127(14):1790-1802) [ABSTRACT FROM AUTHOR]