Gerardo Rodriguez

Myelodysplastic syndrome (MDS) is a group of rare disorders that results in ineffective hematopoiesis and can progress into acute myeloid leukemia (AML). Spliceosomal mutations occur in about 50% of MDS patients, with SF3B1 being the most commonly mutated splicing factor protein. The purpose of this study was to investigate the functional impact of aberrant alternative splicing resulting from mutant SF3B1. The TGen Bisbee pipeline was used to analyze RNAseq data from K562 cells that expressed wild-type (WT) and mutant SF3B1 K700E, and identify alternative splicing events that were differentially expressed in the mutant cells compared to WT. Using the predicted location of these splice events within the protein sequences, we mapped overlapping protein domains from the Ensembl/Pfam database. Our results suggest some protein domain families are more frequently impacted than others in the presence of mutant SF3B1, including the zinc finger domain family which is known to be associated with cellular development and differentiation. When alternatively spliced domains in the mutant cells were mapped to biological processes, we found that 23 were involved with positive regulation of histone H3-K79 methylation. A lack of H3-K79 methylation has been previously associated with defective erythropoiesis in mice models with MDS. We intend to incorporate our domain annotation workflow as a module in the TGen Bisbee Pipeline to help annotate alternatively spliced protein domains in other cancers.