Heterogeneous sensitivity of human acute myeloid leukemia to β-catenin down-modulation.
Heterogeneous sensitivity of human acute myeloid leukemia to β-catenin down-modulation.
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作者：
Wnt/β-连环蛋白途径的失调已经在各种恶性肿瘤中观察到，包括急性髓性白血病（AML），其中β-连环蛋白的过表达是独立的不良预后因素。发现β-连环蛋白在绝大多数AML样品中上调，并且与正常骨髓CD 34+细胞相比更频繁地定位于白血病干细胞的细胞核中。使用短发夹RNA（shRNA）慢病毒方法敲低β-连环蛋白，加速ATRA诱导的分化并损害HL 60白血病细胞系的增殖。使用这些细胞的体内定量追踪，我们观察到当β-连环蛋白沉默时，异种移植后植入潜力降低。然而，当研究原代AML细胞时，尽管β-连环蛋白的有效下调，我们没有观察到它们在MS-5基质上的体外长期维持或它们在体内的植入潜力的任何损害。总之，这些结果表明，尽管在AML中β-连环蛋白频繁上调，但白血病起始细胞可能不会对该途径“上瘾”，因此针对β-连环蛋白的靶向治疗可能不会在所有患者中成功。
Dysregulation of the Wnt/ß-catenin pathway has been observed in various malignancies, including acute myeloid leukemia (AML), where the over-expression of ß-catenin is an independent adverse prognostic factor. ß-catenin was found up-regulated in the vast majority of AML samples and more frequently localized in the nucleus of leukemic stem cells compared to normal bone marrow CD34+ cells. The knockdown of ß-catenin, using a short hairpin RNA (shRNA) lentiviral approach, accelerates ATRA-induced differentiation and impairs the proliferation of HL60 leukemic cell line. Using in vivo quantitative tracking of these cells, we observed a reduced engraftment potential after xenotransplantation when ß-catenin was silenced. However when studying primary AML cells, despite effective down-regulation of ß-catenin we did not observe any impairment of their in vitro long-term maintenance on MS-5 stroma nor of their engraftment potential in vivo. Altogether, these results demonstrate that despite a frequent ß-catenin up-regulation in AML, leukemia initiating cells might not be ‘addicted’ to this pathway and thus targeted therapy against ß-catenin might not be successful in all patients.
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DOI：
10.1073/pnas.0604579103
发表时间：
2006-11-07
影响因子：
11.1
作者：
Bansal, Dimple;Scholl, Claudia;Huntly, Brian J. P.
通讯作者：
Huntly, Brian J. P.
影响因子：
20.3
作者：
Taussig, David C.;Vargaftig, Jacques;Bonnet, Dominique
通讯作者：
Bonnet, Dominique
影响因子：
158.5
作者：
Jamieson, CHM;Ailles, LE;Weissman, IL
通讯作者：
Weissman, IL
影响因子：
64.8
作者：
Reya, T;Duncan, AW;Weissman, IL
通讯作者：
Weissman, IL
影响因子：
20.3
作者：
Ailles, LE;Gerhard, B;Hogge, DE
通讯作者：
Hogge, DE