Synergistic intragenic epigenetic deregulation by IDH2 and SRSF2 mutations causes mis-splicing of key transcriptional regulators

Genes affecting DNA methylation (DNAme) are frequently comutated with splicing factors in acute myeloid leukemia (AML) and associate with more aggressive phenotypes. To elucidate the underlying molecular mechanisms, we deeply profiled wild-type and IDH2^R140Q/SRSF2^P95 single- or double-mutant AMLs. We find a unique set of mis-spliced genes and differentially methylated CpGs in double mutants. Mis-spliced exons are enriched in CCNG splicing enhancers and in the corresponding DNAme changes. Using a machine learning model, we can accurately predict exon inclusion levels from proximal CpGs. These CpGs are more likely to overlap footprints of RNA binding and chromatin-modifying complexes but not transcription factors. We also report unique gene expression profiles associated with each genotype; however, the differentially expressed genes do not overlap with mis-spliced transcripts. Instead, the mis-spliced genes encode for proteins that interact with the complexes regulating these differentially expressed genes. Thus, aberrant DNAme and splicing lead to the mis-splicing of key regulatory complexes, resulting in the aberrant gene expression profiles characteristic of these AMLs.