Coordinated Alterations in RNA Splicing and Epigenetic Regulation Drive Leukemogenesis

Transcription and pre-mRNA splicing are key steps in the control of gene expression in eukaryotic cells and mutations in genes regulating each of these processes are common in leukemia1,2. Despite the frequent overlap of mutations affecting epigenetic regulation and RNA splicing in leukemia, how these processes influence one another to promote leukemogenesis is not understood and functional evidence that mutations in RNA splicing factors initiate leukemia in vivo does not exist. Here through analyses of acute myeloid leukemia (AML) patient transcriptomes, we identified frequent overlap of mutations in genes encoding the citric acid cycle enzyme IDH2 and the RNA splicing factor SRSF2 which together promote leukemogenesis through coordinate effects on the epigenome and RNA splicing.