Molecular Basis for Myelodysplasia Induced by U2AF1 Mutations

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Title: Molecular Basis for Myelodysplasia Induced by U2AF1 Mutations Abstract Myelodysplastic syndromes (MDS) are clonal hematologic disorders characterized by cytopenia and dysplasia of myeloid linage cells with an increased risk of transformation to acute myeloid leukemia. Current therapies are inadequate to treat MDS. This underscores a need to better understand the molecular mechanism of MDS and identify new therapeutic targets in MDS. Mutations in the genes encoding RNA splicing factors (U2AF1, SRSF2, SF3B1 or ZRSR2) are frequently observed in MDS. U2AF1 is involved in the recognition of the 3’ splice site required for recruitment of the U2 snRNP during pre-mRNA splicing. U2AF1 mutations have been identified in ~11% cases of MDS. However, the functional roles of U2AF1 mutations in MDS and the mechanism by which U2AF1 mutations contribute to MDS pathogenesis remain unclear. To determine the roles of mutant U2AF1 in MDS, we have generated a novel conditional U2AF1-Q157R knock-in mouse. In preliminary studies, we have observed that hematopoietic expression of U2AF1-Q157R mutant results in a macrocytic anemia, erythroid dysplasia and expansion of hematopoietic stem cells (HSC) in the bone marrow. We also have observed that concurrent loss of EZH2 and expression of U2AF1-Q157R mutant promotes rapid progression of MDS. We hypothesize that U2AF1 mutations trigger RNA splicing alterations, gene expression changes, DNA damage and replication stress in HSPC leading to aberrant hematopoiesis, and U2AF1 mutations cooperate with epigenetic regulator mutations in the progression of MDS. To test our hypothesis, we propose three Specific Aims. In Aim 1, we will investigate the consequences of U2AF1-Q157R mutation and underlying molecular mechanisms in myelodysplasia. In Aim 2, we will determine the biological and molecular basis for synergy between U2AF1 mutations and co-occurring epigenetic regulator mutations in the pathogenesis of MDS. In Aim 3, we will identify and test therapeutic strategies for U2AF1 mutant MDS. Results from these studies will provide new insights into the molecular pathogenesis of MDS and may lead to new therapeutic approach for treatment of MDS.