CD43调控t(8;21)阳性急性髓系白血病细胞干性维持的机制研究

AML1/ETO融合蛋白由t(8;21)染色体异位产生(AML-M2b)，是急性髓系白血病中发生率最高的一种染色体异常。M2b白血病的研究主要集中在致病分子机制，但至今没有突破性的治疗方法出现。研究表明白血病细胞是等级性的异质性群体，其恶性造血的维持依赖于白血病干细胞（LSCs）的持续增殖，而LSCs对现行治疗的抵抗是白血病复发的主要原因。目前对于M2b白血病细胞干性维持机制知之甚少，我们前期对M2b小鼠模型（AE9a）的研究证实CD43是AE9a白血病细胞干性相关的特异性表面标记物，AEa包括CD43+c-Kit+、CD43+c-Kit-、CD43-c-Kit-三个群体，它们在表型及生物学功能上均表现出异质性。本课题拟通过该小鼠模型：1) 明确CD43对AE9a白血病细胞干性的影响；2）阐明CD43对AE9a干性调控的分子机制，我们相信本课题为研究根治AML-M2b的疗法提供新的思路。

The AML1/ETO fusion transcription factor is generated by the t(8;21) translocation (AML-M2b)，which represents the most frequent chromosomal abnormality in AML . The current treatments of AML are mainly chemotherapy and bone marrow transplantation . Researches on AML-M2b mainly focus on the molecular mechanisms of pathogenesis, whereas there is no breakthrough treatment emerging. Recent studies indicate that leukemia cells are arranged in a hierarchy with leukemia stem cells(LSCs) giving rise to more differentiated bulkcells, and the maintenance of malignant hematopoiesis depends on the continued proliferation of LSCs, and LSCs are frequently resistant to standard chemotherapy and their persistence after therapy is a common cause of relapse. However, we know very little about how leukemic stemness is molecularly modulated. Our preliminary studies on AML-M2b mouse model(AE9a) confirmed that CD43 was a specific surface marker associated with the stemness of leukemia cells, and AE9a leukemia cells included three groups, as CD43+c-Kit+, CD43+c-Kit. -, CD43-c-Kit -, which showed heterogeneity in phenotype and biological function. We attempt to figure out: 1) whether CD43 effects the stemness of AE9a leukemia cells; 2) the essential mechanisms that regulate the stemness of AE9a by CD43. We believe that conduction of this proposed study will provide new insights into novel therapeutic strategies of eradication of AML-M2b LSCs.