Targeting primitive chronic myeloid leukemia cells by effective inhibition of a new AHI-1-BCR-ABL-JAK2 complex.
Targeting primitive chronic myeloid leukemia cells by effective inhibition of a new AHI-1-BCR-ABL-JAK2 complex.
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DOI：
10.1093/jnci/djt006
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发表时间：
2013-03-20
期刊：
影响因子：
--
通讯作者：
Jiang X
中科院分区：
文献类型：
--
作者：
Chen M;Gallipoli P;DeGeer D;Sloma I;Forrest DL;Chan M;Lai D;Jorgensen H;Ringrose A;Wang HM;Lambie K;Nakamoto H;Saw KM;Turhan A;Arlinghaus R;Paul J;Stobo J;Barnett MJ;Eaves A;Eaves CJ;Holyoake TL;Jiang X
甲磺酸伊马替尼(IM)诱导慢性粒细胞白血病(CML)临床缓解Abelson辅助整合位点1(AHI-1)癌蛋白与bcr-abl和Janus kinase2(JAK2)相互作用，介导原始CML细胞的IM反应，但这种相互作用复合体对ABL和JAK2抑制剂的反应的影响尚不清楚。对AHI-1-BCR-ABL-JAK2相互作用复合体进行突变分析和免疫共沉淀分析。在BCR-ABL+细胞、原代CML干/祖细胞和免疫缺陷的NSG小鼠中，研究了该复合体在调节对ABL和JAK2抑制剂的反应或抵抗中的作用。所有的统计检验都是双面的。AHI-1的WD40重复结构域与BCR-ABL相互作用，而N-末端与JAK2相互作用；这些相互作用的缺失显著增加了CML细胞对IM的敏感性。与单一药物相比，联合使用IM和口服生物可用选择性JAK2抑制剂(TG101209[TG])可显著诱导AHI-1过表达和IM耐药细胞的死亡，并提高白血病小鼠的存活率(联合用药与单独用药相比：63天比53天，比率=0.84，95%可信区间[CI]=0.6至1.1，P=0.004；vs IM：57天，比率=0.9，95%CI=0.61至1.2，P=0.003)。联合治疗还在统计学上显著促进了CD34+白血病干/祖细胞的凋亡，并消除了它们在NSG小鼠中长期引发白血病的活性。重要的是，这种方法对那些后来被证明对IM治疗有抵抗力的患者的治疗未成熟的CML干细胞是有效的。同时靶向CML干细胞/祖细胞中的bcr-abl和JAK2活性可能会改善注定会出现IM耐药的患者的预后。
Imatinib mesylate (IM) induces clinical remission of chronic myeloid leukemia (CML). The Abelson helper integration site 1 (AHI-1) oncoprotein interacts with BCR-ABL and Janus kinase 2 (JAK2) to mediate IM response of primitive CML cells, but the effect of the interaction complex on the response to ABL and JAK2 inhibitors is unknown. The AHI-1–BCR-ABL–JAK2 interaction complex was analyzed by mutational analysis and coimmunoprecipitation. Roles of the complex in regulation of response or resistance to ABL and JAK2 inhibitors were investigated in BCR-ABL + cells and primary CML stem/progenitor cells and in immunodeficient NSG mice. All statistical tests were two-sided. The WD40-repeat domain of AHI-1 interacts with BCR-ABL, whereas the N-terminal region interacts with JAK2; loss of these interactions statistically significantly increased the IM sensitivity of CML cells. Disrupting this complex with a combination of IM and an orally bioavailable selective JAK2 inhibitor (TG101209 [TG]) statistically significantly induced death of AHI-1–overexpressing and IM-resistant cells in vitro and enhanced survival of leukemic mice, compared with single agents (combination vs TG alone: 63 vs 53 days, ratio = 0.84, 95% confidence interval [CI] = 0.6 to 1.1, P = .004; vs IM: 57 days, ratio = 0.9, 95% CI = 0.61 to 1.2, P = .003). Combination treatment also statistically significantly enhanced apoptosis of CD34+ leukemic stem/progenitor cells and eliminated their long-term leukemia-initiating activity in NSG mice. Importantly, this approach was effective against treatment-naive CML stem cells from patients who subsequently proved to be resistant to IM therapy. Simultaneously targeting BCR-ABL and JAK2 activities in CML stem/progenitor cells may improve outcomes in patients destined to develop IM resistance.
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