复发是Ph+ALL治疗失败的主要原因，白血病启动细胞（LPC）是白血病复发的根源。本课题组前期通过人源化小鼠模型鉴定、临床队列研究证实CD34+CD38-CD58-细胞为Ph+ALL白血病启动细胞，为针对LPC治疗优化的实验研究奠定了基础。预实验发现，①LPC静止期比例增高，对伊马替尼敏感性降低；②BCR-ABL下调，JAK2、STAT3上调，提示LPC可能存在非BCR-ABL依赖的JAK2-STAT3通路激活，并介导耐药和复发。因而，JAK2-STAT3通路有望成为Ph+ALL白血病启动细胞的治疗靶点。本研究旨在通过体外实验、人源化Ph+ALL小鼠模型和注册临床试验，在LPC水平探索与Ph+ALL复发相关的关键信号通路，阐明达沙替尼分别联合JAK2、STAT3或STAT5抑制剂，干扰素-α联合伊马替尼的抗Ph+ALL白血病启动细胞作用及其机制，为优化Ph+ALL复发防治策略奠定基础。

Relapse, the major cause of treatment failure in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL), seriously affects the long-term survival of Ph+ALL patients. Leukemia propagating cells (LPC), defined by their ability to initiate human leukemia and self-renew in immunocompromised mice, almost equal to leukemia stem cells. Relapse of Ph+ALL may result from the persistence of LPC. Using an anti-CD122-conditioned NOD/SCID xenograft mouse assay, we have recently reported that LPC are enriched in the CD34+CD38-CD58- fraction in human Ph+ALL. Further cohort study demonstrated that Ph+ALL patients with LPC (CD34+CD38-CD58- cells) phenotype at diagnosis exhibited significantly higher cumulative incidence of relapse than the other phenotype group. Our preliminary data showed that an enrichment of the G0 phase of cell cycle, less sensitive to imatinib, the reduced expression of BCR-ABL, and the increased expression of JAK2 and STAT3 in LPC (CD34+CD38-CD58- cells), suggesting the existence of BCR-ABL kinase-independent tyrosine kinase inhibitor (TKI) resistance in Ph+ALL LPC. Moreover, the JAK2-STAT3 pathway promises to be a major determinant of LPC-mediated relapse in Ph+ALL. Based on our previous work, this study attempts to explore the important pathways for providing survival signals to Ph+ALL LPC. Furthermore, the effects of dasatinib alone or in combination with the inhibitors of either JAK, STAT3 or STAT5; interferon-αcombined with TKI, targeting the Ph+ALL LPC and their potential mechanisms will be evaluated in vitro study, in humanized Ph+ALL mouse model and the registered clinical trial. The successful implementation of this pre-clinical study may provide novel therapeutic strategies for the treatment of relapse in Ph+ALL, and it may eventually improve the clinical outcomes of Ph+ALL patients.