title: Epigenetic modifications of splicing factor genes in myelodysplastic syndromes and acute myeloid leukemia.
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.
authors.affiliation: Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, New South Wales, Australia; Sydney Medical School, University of Sydney, Camperdown, New South Wales, Australia.
authors.forename: Justin J-L
authors.initials: JJ
authors.lastname: Wong
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Lau
authors.forename: Natalia
authors.initials: N
authors.lastname: Pinello
authors.forename: John E J
authors.initials: JE
authors.lastname: Rasko
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D020868:Gene Silencing; D056426:Genetic Loci; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D012326:RNA Splicing; D012261:Ribonucleoproteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D009687:Nuclear Proteins; D012261:Ribonucleoproteins; C484334:ZRSR2 protein, human
keywords: Acute myeloid leukemia; DNA hypermethylation; epigenetics; myelodysplastic syndromes; splicing factors