c-Kit在急性早幼粒细胞白血病起始细胞中的作用

目的:探讨小鼠造血系干祖细胞表面标志c-Kit在急性早幼粒细胞白血病(APL)起始细胞中的作用。方法:以人源移动抑制因子相关蛋白8基因启动子表达的人源早幼粒细胞白血病-维A酸受体α融合基因(hMRP8-hPML-RAR)转基因所致小鼠APL为研究模型,研究APL起始细胞的表面标志。结果:发现在APL小鼠模型体内存在一群以c-Kit+为标志的白血病起始细胞(LIC)。通过体外培养,发现LIC在失去肿瘤微环境支持后由c-Kit+细胞向c-Kit-细胞分化,同时逐渐丧失白血病致病力。c-Kit的磷酸化位点抑制剂伊马替尼和小发夹RNA(shRNA)虽均抑制c-Kit功能和(或)表达,但并不能明显影响白血病致病力。结论:肿瘤微环境在APL起始细胞致瘤力的维持上有非常重要的作用,在白血病致病力的维持上c-Kit可能并不是一主导功能因素。

Role of c-Kit in acute promyelocytic leukemia-initiating cells

Objective:To investigate the role of c-Kit,a surface marker of mouse hematopoietic stem/progenitor cells,in acute promyelocytic leukemia-initiating cells(LIC).Methods:Mouse acute promyelocytic leukemia(APL) constructed transgenically by human promyelocytic leukemia-retinoic acid receptor(hMRP8-hPML-RAR)expressed by promoter of human migration inhibitory factor-related protein 8 gene was used as the investigating model.Results:There was a subset of c-Kit+ LIC,and it was differentiated into c-Kit-subset during in vitro culture without tumor micro-environmental support and lost its leukemia initiating ability.c-Kit phosphorylation site inhibitor imatinib and knockdown of c-Kit expression by short hairpin RNA(shRNA) had no effect on leukemia initiating ability.Conclusions:These results suggested that tumor microenvironment played an important role in the maintenance of leukemia initiating ability,and c-Kit might not be a key factor in maintaining the leukemia initiating ability.