FUS-ERG融合蛋白协同PTPN11突变致白血病机制研究

t(16;21)(p21;q22)是急性白血病中一种罕见的再现性染色体易位，形成FUS-ERG融合基因。目前该类患者生存预后极差，而且FUS-ERG融合蛋白的生物学功能特征及其致白血病机制等尚不明确，特别是FUS-ERG融合基因小鼠模型的建立尚未成功，提示FUS-ERG融合蛋白致白血病过程中需要协同事件的参与。在前期工作中，申请人筛选到一组伴有t(16;21)(p21;q22)的急性白血病病例，通过全外显子测序和高通量靶向捕获测序技术，发现其中PTPN11基因的突变率高达30%，提示PTPN11突变在FUS-ERG融合蛋白致白血病过程中可能发挥非常重要的作用。本课题拟深入探讨FUS-ERG融合蛋白协同PTPN11突变致白血病的作用机制，以及使用PTPN11抑制剂SHP099对疾病的靶向治疗作用。本研究将为深入理解FUS-ERG融合蛋白致白血病的发病机制、寻找新的治疗靶点提供理论和实验依据。

t(16;21)(p21;q22) is a rare recurrent chromosomal abnormality in acute leukemia. The translocation results in a FUS-ERG fusion gene. The t(16;21)-positive AL had a poor prognosis. However, the biological characteristics and the leukemogenesis mechanism of FUS-ERG fusion protein is not clear for now. Especially the bone marrow transplant and knock-in mouse model of FUS-ERG run into a failure. This suggests that important collaborative events are required for leukemogenesis of FUS-ERG fusion protein. We have found acute leukemia cases with t(16;21)(p21;q22), comprising the largest number from a singer center internationally. Through whole-exome sequencing and target next generation sequencing, we identified that PTPN11 mutation rate reaches to 30%. This indicates that PTPN11 mutation may play an important part in the pathogenesis of FUS-ERG fusion protein. This research aims to explore the cooperation of FUS-ERG fusion gene harbored PTPN11 mutation in leukemogenesis, and the targeted therapeutic effect of PTPN11 inhibitor shp099 on the disease. This study will provide theoretical and experimental basis for further understanding the pathogenesis of leukemia induced by FUS-ERG fusion protein and finding new therapeutic targets.