Molecular mechanisms of clonal expansion in myelodysplasia

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Frequent pathway mutations involving multiple components of the RNA splicing machinery is considered one of the most important genetic events in MDS. But the molecular mechanisms of these alterations in the pathogenesis of MDS are still unknown. In this study we investigated the functional role of these mutants in hematopoiesis using mice model that focused on clonal expansion of mutated cells. We analyzed the hematological phenotype of Sf3b1 hetero mice, and SF3B1 plays an important role in the regulation of hematopoietic stem cells (HSCs), whereas SF3B1 haploinsufficiency is not associated with the MDS phenotype. Loss of function mutation of TET2 are often co-existed in MDS cases with RNA spliceosome mutation, and that we performed the competitive stem cell transplantation using spliceosome mutant transduced HSCs from TET2 knockout mice or wild type mice. But there are no evidence of growth advantage of HSCs with RNA spliceosome mutation in spite of TET2 deletion in this model.