Molecular mechanisms of clonal expansion in myelodysplasia

涉及RNA剪接机制多个组成部分的频繁路径突变被认为是MDS最重要的遗传事件之一。但这些改变在MDS发病机制中的分子机制仍不清楚。在这项研究中，我们利用专注于突变细胞克隆性扩增的小鼠模型，研究了这些突变在造血中的功能作用。我们分析了SF3B1异种小鼠的血液学表型，发现SF3B1在造血干细胞(HSCs)的调节中起着重要作用，而SF3B1单倍体缺陷与MDS表型无关。在伴有RNA剪接体突变的MDS患者中，常存在TET2功能缺失突变，我们采用TET2基因敲除小鼠或野生型小鼠转导的剪接体突变的HSCs进行竞争性干细胞移植。但在该模型中，尽管TET2缺失，但没有证据表明具有RNA剪接体突变的HSCs具有生长优势。

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.