Accession Number : AD1039463


Title :   The Role of U2AF1 Mutations in the Pathogenesis of Myelodysplastic Syndromes


Descriptive Note : Technical Report,30 Sep 2013,29 Sep 2016


Corporate Author : Washington University St. Louis United States


Personal Author(s) : Walter,Matthew J


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/1039463.pdf


Report Date : 01 Dec 2016


Pagination or Media Count : 32


Abstract : U2AF1 mutations occur in up to 11% of myelodysplastic syndrome (MDS) patients. To study the effects of the most common U2AF1 mutation, U2AF1(S34F), on hematopoiesis and pre-mRNA splicing in vivo, we created doxycycline-inducible U2AF1(WT) and U2AF1(S34F) transgenic mice. Following transgene induction, U2AF1(S34F) mice have reduced WBCs, increased hematopoietic stem/progenitor cells, and increased HSC cell cycling compared to U2AF1(WT) mice. U2AF1(S34F) stem cells are at a competitive disadvantage compared to control cells, suggesting that the increase in HSC cell cycling following U2AF1(S34F) expression may lead to stem cell exhaustion. Next, we compared RNA splicing in progenitor cells from U2AF1(S34F) and U2AF1(WT) mice using whole transcriptome RNA-seq. We identified 460 splicing junctions that were differentially expressed in U2AF1(S34F) samples compared to U2AF1(WT). We validated several homologous dysregulated junctions (i.e., across species) in MDS patient bone marrow samples that have mutant U2AF1(S34F) versus U2AF1(WT). 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.


Descriptors :   mutations , Hematopoiesis , rna sequence analysis , Ribonucleic acids , CANCER , bone marrow


Subject Categories : Medicine and Medical Research


Distribution Statement : APPROVED FOR PUBLIC RELEASE