Mutations Affecting Splicing and Epigenetics Promote Leukemogenesis

Mutations that affect the regulation of transcription or RNA splicing are common in leukemia; often, mutations affecting both processes are found in the same patients. In an analysis of RNA sequencing (RNA-seq) data from patients with acute myeloid leukemia (AML), Yoshimi, Lin, Wiseman, and colleagues found evidence of mutations in the splicing-factor gene SRSF2 in several patients. Of patients with mutated SRSF2, 47% also had mutated IDH2, encoding the mitochondrial enzyme isocitrate dehydrogenase 2, mutations in which often result in DNA hypermethylation. Experiments in mice transplanted with bone marrow overexpressing mutant human IDH2 with or without expression of mutant Srsf2 demonstrated a cooperative effect between mutations in the two genes in promoting leukemogenesis. RNA-seq data from patients with AML indicated that cells bearing mutations in both SRSF2 and IDH2 had increased splicing errors compared with cells bearing mutations in SRSF2 alone. Reverse-transcriptase PCR experiments using primary AML samples revealed aberrant splicing of INTS3, encoding a component of the transcription-regulating Integrator complex. Chromatin immunoprecipitation with DNA sequencing experiments using SRSF2-mutant cell lines as well as primary samples from patients with AML implied dysfunction of the entire Integrator complex in SRSF2-mutant cells and suggested a connection between increased DNA methylation and stalling of RNA polymerase II in SRSF2 and IDH2 double-mutant AML cells. Further, loss of INTS3 associated with splicing errors caused by mutant IDH2 or SRSF2 was shown to contribute to leukemogenesis in mice. Notably, in patient AML samples, incorrect splicing of INTS3 was present not only in IDH2- and SRSF2-mutant cases, but also in other cases—but not in healthy blood cells. Together, these findings provide mechanistic insight into the role of aberrant splicing and transcriptional misregulation in leukemogenesis and, especially given that approximately half of patients with leukemia have mutations in IDH2, suggest that therapies that modulate splicing may be worth exploring.

Yoshimi A, Lin KT, Wiseman DH, Rahman MA, Pastore A, Wang B, et al. Coordinated alterations in RNA splicing and epigenetic regulation drive leukaemogenesis. Nature 2019;574:273–7.

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