Epigenetic modifications of splicing factor genes in myelodysplastic syndromes and acute myeloid leukemia

Cancer Science

Justin J.-L. Wong¹  Katherine A. Lau¹  Natalia Pinello¹ 

[1] Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, New South Wales, Australia

关键词: Acute myeloid leukemia;    DNA hypermethylation;    epigenetics;    myelodysplastic syndromes;    splicing factors;   

DOI  :  10.1111/cas.12532

来源: Wiley

【 摘 要 】

Abstract

Somatic mutations in splicing factor genes have frequently been reported in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Although aberrant epigenetic changes are frequently implicated in blood cancers, their direct role in suppressing one or both alleles of critical splicing factors has not been previously examined. Here, we examined promoter DNA hypermethylation of nine splicing factors, SF3B1, SRSF2, U2AF1, ZRSR2, SF3A1, HNRNPR, MATR3, ZFR, and YBX3 in 10 leukemic cell lines and 94 MDS or AML patient samples from the Australasian Leukemia and Lymphoma Group Tissue Bank. The only evidence of epigenetic effects was hypermethylation of the YBX3 promoter in U937 cells in conjunction with an enrichment of histone marks associated with gene silencing. In silico analysis of DNA methylation data for 173 AML samples generated by the Cancer Genome Atlas Research Network revealed promoter hypermethylation of the gene encoding Y box binding protein 3, YBX3, in 11/173 (6.4%) AML cases, which was significantly associated with reduced mRNA expression (P < 0.0001). Hypermethylation of the ZRSR2 promoter was also detected in 7/173 (4%) cases but was not associated with decreased mRNA expression (P = 0.1204). Hypermethylation was absent at the promoter of seven other splicing factor genes in all cell lines and patient samples examined. We conclude that DNA hypermethylation does not frequently silence splicing factors in MDS and AML. However, in the case of YBX3, promoter hypermethylation-induced downregulation may contribute to the pathogenesis or maintenance of AML.

【 授权许可】

CC BY-NC-ND   
© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

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