Alternative Mrna Splicing Redefines The Landscape Of Commonly Dysregulated Genes Across The Acute Myeloid Leukemia Patient Population.
Most genes associated with acute myeloid leukemia (AML) are mutated in less than 10% of patients, suggesting that alternative mechanisms of gene disruption contribute to this disease. Here, I investigate pre-mRNA splicing events with significant variation and striking coregulation across distinct AML cohorts. I find that most splicing events are expected to alter the expression of a subset of AML-associated genes independent of known somatic mutations. In particular, I highlight that aberrant splicing triples the number of patients with reduced functional EZH2 protein compared with that predicted by somatic mutation alone. In addition, I unexpectedly find that transcripts encoding the nonsense-mediated RNA decay factor DHX34 exhibit widespread alternative splicing in sporadic AML, resulting in a premature stop codon that phenocopies the loss-of-function germline mutations observed in familial AML. The identification of DHX34 splicing event that functionally downregulates the nonsense-mediated mRNA degradation (NMD) pathway motivated a query of splicing variations in an additional set of related NMD factors. Although no particular study has highlighted genetic mutations in the queried NMD factors, I find significant variation at the level of mRNA splicing that is expected to have further deleterious effects across AML patients. Together, these results demonstrate that classical mutation analysis underestimates the burden of functional gene disruption in AML and highlight the importance of assessing the contribution of alternative splicing to gene dysregulation in human disease.