组蛋白修饰和选择性剪接是真核基因表达过程中相互协调、密切联系的重要调节机制。ASXL1和SRSF2分别编码组蛋白修饰和选择性剪接的关键调节因子，是髓系肿瘤中常见的突变基因，尤其在MDS/MPN患者中突变频率很高，且常以共突变形式存在。但是ASXL1与SRSF2共突变是否协同参与了疾病的发生发展尚无报道。我们前期建立了Asxl1和Srsf2双突变小鼠，初步结果显示该小鼠发病类型以MDS/MPN为主，生存期较单突变小鼠显著缩短，易发生白血病转化。本研究从临床问题出发，拟通过分析Asxl1与Srsf2共突变对小鼠疾病进程及造血干/祖细胞的影响，阐明ASXL1和SRSF2共突变在MDS/MPN发病中的作用及内在机制，探索相应的靶向治疗策略。这一研究不但加深我们对MDS/MPN疾病表现和转归的理解，也可为携带ASXL1和SRSF2共突变的其它髓系肿瘤研究提供新的思路，最终为相关临床治疗提供理论依据。

Histone modifications are associated with transcription, which are intimately coupled with RNA splicing in the process of eukaryotic gene expression. ASXL1 and SRSF2 are key regulators in histone modification and alternative splicing, respectively. Genes encoding ASXL1 and SRSF2 are frequently mutated in myeloid malignancies, and especially in patients with myelodysplastic/myeloproliferative neoplasm (MDS/MPN). There is a high coincidence of ASXL1 mutation occurred with SRSF2 mutation in MDS/MPN, however, the cellular and molecular mechanisms underlying the pathogenesis associated with concomitant ASXL1 and SRSF2 mutations are unknown and remain to be elucidated. We have established a compound mouse model in which Asxl1 and Srsf2 are double mutated. In this study, we will analyze the effects of concomitant ASXL1 and SRSF2 mutations on disease progression, biological function of hematopoietic stem/progenitor cells, and the underlying molecular mechanisms in the pathogenesis of MDS/MPN. Understanding the biological contribution of concomitant ASXL1 and SRSF2 mutations will shed light on the effect of cooperation between epigenetic alterations and RNA splicing on the pathogenesis of myeloid malignancies including MDS/MPN, and provide further insight in the diagnosis, prognosis and targeting therapy of patients carried ASXL1 and SRSF2 mutations.