巨细胞病毒再激活通过阻止T细胞功能耗竭降低Allo-HSCT后AML复发的机制研究

异基因造血干细胞移植（allo-HSCT）是治愈血液肿瘤有效乃至唯一的方法，移植后白血病复发是其失败最主要原因，但机制不清。急性髓系白血病（AML）患者移植后巨细胞病毒（CMV）再激活可降低白血病复发，但机制不清。我们及相关研究者发现：T细胞耗竭与移植后白血病复发相关；持续CMV感染能激活T细胞功能；AP-1家族中c-Jun缺失可导致T细胞耗竭。据此我们提出移植后CMV再激活通过上调T细胞c-Jun表达阻止T细胞耗竭是其降低白血病复发机制之一的科学假说。本课题拟借助临床队列、体内外实验和动物模型研究：移植后CMV再激活对T细胞耗竭及相关基因表达和白血病复发的影响及机制；CMV再激活通过c-Jun途径调节T细胞耗竭的机制；移植后CMV再激活患者T细胞对白血病细胞的杀伤及机制。揭示CMV再激活降低移植后白血病复发的机理、移植后T细胞耗竭的机制，为构建移植后白血病复发防治新方法提供理论依据。

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective or even the only curative way for malignant hematologic diseases. However, disease relapse after transplantation is the major cause of treatment failure, but the mechanism remains unclear. In patients with acute myeloid leukemia (AML), Cytomegalovirus (CMV) reactivation after allo-HSCT can reduce relapse after transplantation, but the mechanism is unknown. Recently, increasing evidence suggests that T cell exhaustion is closely related to post-transplantation relapse; Persistent CMV infection can activate T cells; And the deficiency of AP-1 factor c-Jun contributes to T cell exhaustion. Based on these, we propose a scientific hypothesis that CMV reactivation may reduce the relapse after allo-HSCT through up-regulating c-Jun expression in T cells and obstructing T cell exhaustion. To validate the hypothesis, we intend to study in vitro, in vivo, animal models, and patients: the effects and mechanisms of CMV reactivation on T cell exhaustion and related gene expression and leukemia relapse after allo-HSCT, the mechanism of CMV reactivation on T cell exhaustion through the c-Jun pathway, the effects and mechanisms of T cells in patients with post-transplantation CMV reactivation against leukemia cells. These studies will reveal the mechanisms of CMV reactivation reducing post-transplantation relapse and T cell exhaustion after transplantation. These studies will also provide the theoretical basis for constructing new methods preventing and treating leukemia relapse after transplantation.