Splicing variations contribute to the functional dysregulation of genes in acute myeloid leukemia
Osvaldo D. Rivera
iRNA COSI, ISMB 2020, RNA2020
Altered pre-mRNA splicing may result in aberrations that phenocopy classical somatic mutations. Despite the importance of RNA splicing, most studies of acute myeloid leukemia (AML) have not broadly explored means by which altered splicing may functionally disrupt genes associated with AML. To address this gap, we investigated the splicing variability of 70 AML-associated genes within RNA-Seq data from 29 in-house AML patient samples (PENN cohort). In brief, using the MAJIQ splicing quantification algorithm, we detected 40 highly variable splicing events across the patients of the PENN cohort, many of which are novel and reduce expression of protein without changing overall transcript abundance. Splicing variability occurred independently of known cis-mutations, thus highlighting pathogenic mechanisms overlooked by standard genetic analyses. We also find these 40 splicing events as significantly more variable within the ~400 patient BEAT-AML cohort when compared to normal CD34+ cells. Furthermore, hierarchical clustering revealed a high degree of correlation between 23 of these 40 splicing events in both the PENN and BEAT-AML cohorts, suggesting a pathogenic co-regulation which is not observed in normal CD34+ cells. Overall, our findings highlight underlying transcriptomic complexity across AML populations and demonstrate how previously unreported splicing variations contribute to protein dysregulation in AML.
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