Splicing Variation Contributes to Functional Dysregulation of Genes in Acute Myeloid Leukemia

Acute Myeloid Leukemia (AML) has been associated with somatic mutations in numerous genes; however, the penetrance of these mutations is low. Here we investigate the contribution of alternative splicing as an additional layer of gene dysregulation in AML. By analyzing splicing variations across two patient datasets, we find a consistent set of splicing events that disrupt the coding potential of a subset of AML-associated genes. Importantly, most of these splicing variations are independent of any currently-identified somatic mutations. We have further validated that for EZH2 and ZRSR2 these splicing events reduce the expression of full-length protein. Together these results highlight the contribution of splicing to gene dysregulation and demonstrate that mutation analysis underestimates the burden of functional gene disruption in patient populations. Overall design: 29 AML samples, 2 normal donors, 2 cel lines