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

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 fac...

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Bibliographic Details
Published in:	Cancer science 2014-11, Vol.105 (11), p.1457-1463
Main Authors:	Wong, Justin J.‐L., Lau, Katherine A., Pinello, Natalia, Rasko, John E. J.
Format:	Article
Language:	eng
Subjects:	Acute myeloid leukemia Adolescent Adult Aged Aged, 80 and over Anemia Cancer Cell Line, Tumor Deoxyribonucleic acid DNA DNA hypermethylation DNA Methylation Epigenesis, Genetic Epigenetics Female Gene Expression Regulation, Leukemic Gene Silencing Genes Genetic Loci Genetic testing Genomes Hematology Humans Leukemia Leukemia, Myeloid, Acute - diagnosis Leukemia, Myeloid, Acute - genetics Lymphoma Male Middle Aged Mutation Myelodysplastic syndrome myelodysplastic syndromes Myelodysplastic Syndromes - diagnosis Myelodysplastic Syndromes - genetics Myeloid leukemia Nuclear Proteins - genetics Original Pathogenesis Patients Promoter Regions, Genetic Ribonucleoproteins - genetics RNA Splicing Splicing factors Young Adult
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Summary:	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
ISSN:	1347-9032 1349-7006