c-Kit在急性早幼粒细胞白血病起始细胞中的作用

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

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。

Objective： To investigate the role of c-Kit, a surface marker of mouse hematopoietic stem/progenitor cells, in acute promyelocytie leukemia-initiating cells （LIC）. Methods： Mouse acute promyelocytic leukemia （APL） constructed transgenically by human promyelocytie 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.