急性淋巴细胞白血病（ALL）异基因造血干细胞移植后复发是影响移植疗效首要障碍，本项目以宏观视角，关注白血病自身生物学特性与机体抗白血病免疫内外调控机制，基于前期研究提出ALL移植后复发存在白血病细胞的克隆演变创新性理论，并筛选出与ALL发生移植后复发相关的PTPN21基因突变；通过对一系列移植免疫反应重要环节的分子研究，提出以NKG2D为核心的免疫网络失衡影响移植后异源反应性T和NK细胞活化，与ALL移植后免疫逃逸有关。本项目拟进一步通过临床、细胞和基因定点突变、基因敲除动物模型研究明确PTPN21基因突变在ALL复发中的分子机制；并利用全基因组外显子测序技术建立基于中国人群遗传背景的ALL移植后复发相关基因突变谱；通过NKG2D为核心的关键性免疫受体在T和NK细胞活化中的作用和机制研究，明确ALL移植后免疫逃逸机制，为深入阐释ALL移植后复发机制、减少复发和提高移植患者生存率提供新理论。

Disease relapse is one of the leading causes of death in patients with acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The mechanisms of leukemia relapse after allo-HSCT involve in the biological characteristics of leukemia cells and the effect of immune defence against leukemia. In our previous study, we performed exome sequencing analyses on matched diagnosis and relapse sample to explore genetic basis of relapse. We found that cells responsible for ALL relapse after allo-HSCT showed different gene mutations to the primary leukemia cells at diagnosis and acquired new gene mutations. We discovered that mutations in the protein tyrosine phosphatase, non-receptor type 21 (PTPN21) gene contributed to ALL relapse after allo-HSCT. On the other hand, we focused on the disability of immune defence against ALL relapse and proposed that NKG2D and other immune receptors dysfunction may play important roles in ALL relapse after allo-HSCT. Based on our previous study findings, in the present study, firstly, we attempt to elucidate the mechanisms of PTPN21 gene mutations in ALL relapse after allo-HSCT by ex vivo cell studies, transplantation animal model studies and gene mutation knock-in mouse model studies.We further screen gene mutations contributing to other subtype-T-ALL relapse after allo-HSCT and obtain the mutation spectrum associated with ALL relapse after allo-HSCT in Chinese population. Secondly, we focus on the roles of NKG2D and other immune receptors in the molecular mechanisms of insensitivity of ALL to the effect of graft versus leukemia after allo-HSCT. Our study may provide valuable information to research of the mechanisms of leukemia relapse after allo-HSCT and contribute to reduce the incidence of relapse and improve the survival of allogeneic hematopoietic stem cell transplantation patients.