期刊
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
卷 96, 期 5, 页码 712-719出版社
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.2010.028605
关键词
adult T-cell leukemia/lymphoma; human T-cell leukemia virus type-1; Enhancer of zeste homolog 2; H3K27me3
类别
资金
- Ministry of Health, Labour, and Welfare of Japan [04010119]
- NIH, Center for Cancer Research, NCI-Frederick
- Grants-in-Aid for Scientific Research [23590641, 22300326] Funding Source: KAKEN
Background Enhancer of zeste homolog 2 is a component of the Polycomb repressive complex 2 that mediates chromatin-based gene silencing through trimethylation of lysine 27 on histone H3. This complex plays vital roles in the regulation of development-specific gene expression. Design and Methods In this study, a comparative microarray analysis of gene expression in primary adult T-cell leukemia/lymphoma samples was performed, and the results were evaluated for their oncogenic and clinical significance. Results Significantly higher levels of Enhancr of zeste homolog 2 and RING1 and YY1 binding protein transcripts with enhanced levels of trimethylation of lysine 27 on histone H3 were found in adult T-cell leukemia/lymphoma cells compared with those in normal CD4(+) T cells. Furthermore, there was an inverse correlation between the expression level of Enhancer of zeste homolog 2 and that of miR-101 or miR-128a, suggesting that the altered expression of the latter miRNAs accounts for the overexpression of the former. Patients with high Enhancer of zeste homolog 2 or RING1 and YY1 binding protein transcripts had a significantly worse prognosis than those without it, indicating a possible role of these genes in the oncogenesis and progression of this disease. Indeed, adult T-cell leukemia/lymphoma cells were sensitive to a histone methylation inhibitor, 3-deazaneplanocin A. Furthermore, 3-deazaneplanocin A and histone deacetylase inhibitor panobinostat showed a synergistic effect in killing the cells Conclusions These findings reveal that adult T-cell leukemia/lymphoma cells have deregulated Polycomb repressive complex 2 with over-expressed Enhancer of zeste homolog 2, and that there is the possibility of a new therapeutic strategy targeting histone methylation in this disease.
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