The Role of U2AF1 Mutations in the Pathogenesis of Myelodysplastic Syndromes
Technical Report,30 Sep 2014,29 Sep 2015
The Washington University Saint Louis United States
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U2AF1 mutations occur in up to 11 of myelodysplastic syndrome MDS patients. To study the effects of the most common U2AF1 mutation, U2AF1S34F, on hematopoiesis and pre-mRNA splicing in vivo, we created doxycycline-inducible U2AF1WT and U2AF1S34F transgenic mice. Following transgene induction, U2AF1S34F mice have reduced WBCs, increased hematopoietic stemprogenitor cells, and increased HSC cell cycling compared to U2AF1WT mice. U2AF1S34F stem cells are at a competitive disadvantage compared to control cells, suggesting that the increase in HSC cell cycling following U2AF1S34F expression may lead to stem cell exhaustion. Next, we compared RNA splicing in progenitor cells from U2AF1S34F and U2AF1WT mice using whole transcriptome RNA-seq. We identified 460 splicing junctions that were differentially expressed in U2AF1S34F samples compared to U2AF1WT. We validated several homologous dysregulated junctions i.e., across species in MDS patient bone marrow samples that have mutant U2AF1S34F versus U2AF1WT. Together, these results suggest that mutant U2AF1 expression contributes to the altered hematopoiesis and pre-mRNA splicing observed in patients with U2AF1 mutations. This study also identifies changes in gene isoform expression unique to U2AF1 mutations that may have functional significance for MDS pathogenesis, which is being investigated in ongoing studies.