Tyrosine kinase inhibition in leukemia induces an altered metabolic state sensitive to mitochondrial perturbations.
Tyrosine kinase inhibition in leukemia induces an altered metabolic state sensitive to mitochondrial perturbations.
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DOI：
10.1158/1078-0432.ccr-14-2146
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发表时间：
2015-03-15
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影响因子：
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通讯作者：
DeGregori J
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作者：
Alvarez-Calderon F;Gregory MA;Pham-Danis C;DeRyckere D;Stevens BM;Zaberezhnyy V;Hill AA;Gemta L;Kumar A;Kumar V;Wempe MF;Pollyea DA;Jordan CT;Serkova NJ;Graham DK;DeGregori J
虽然酪氨酸激酶抑制剂（TKI）可以有效地治疗白血病，但对于许多晚期BCR-ABL+白血病或急性髓系白血病（AML）患者来说，它们不能完全消除白血病细胞并实现持久的缓解。通过大规模合成致死性RNAi筛选，我们发现丙酮酸脱氢酶是丙酮酸进入线粒体三羧酸循环的限制酶，对BCR-ABL抑制下慢性髓系白血病细胞的存活至关重要。在这里，我们研究了线粒体代谢在TK抑制下Ph+白血病和AML存活中的作用。检测Ph+癌细胞系、AML细胞系、白血病异种移植物、脐带血、患者标本。我们发现线粒体atp合成酶抑制剂oligomycin-A在体外使白血病细胞对TKI显着增敏。令人惊讶的是，低霉素a使白血病细胞对BCR-ABL抑制敏感，浓度低于抑制呼吸所需浓度的100 - 1000倍。Oligomycin-A与TKI联合治疗可迅速导致线粒体膜去极化，降低ATP水平，促进超氧化物的产生和白血病细胞凋亡。重要的是，在小鼠模型和原发性母细胞危像CML样本中，寡霉素a增强了TKI对BCR-ABL+白血病细胞的消除。此外，在体外和体内实验中，oligomycin-A与FLT3 TKI联合使用时，也极大地增强了FLT3依赖性AML细胞的消除。TKI治疗白血病细胞创造了一种新的代谢状态，对特定的线粒体扰动高度敏感。因此，靶向线粒体代谢作为辅助治疗可以改善BCR-ABL+和FLT3ITD白血病患者对TKI的治疗反应。
Although tyrosine kinase inhibitors (TKI) can be effective therapies for leukemia, they fail to fully eliminate leukemic cells and achieve durable remissions for many patients with advanced BCR-ABL+ leukemias or acute myeloid leukemias (AML). Through a large-scale synthetic lethal RNAi screen, we identified pyruvate dehydrogenase, the limiting enzyme for pyruvate entry into the mitochondrial tricarboxylic acid cycle, as critical for the survival of chronic myeloid leukemia cells upon BCR-ABL inhibition. Here we examined the role of mitochondrial metabolism in the survival of Ph+ leukemia and AML upon TK inhibition. Ph+ cancer cell lines, AML cell lines, leukemia xenografts, cord blood, patient samples were examined. We showed that the mitochondrial ATP-synthase inhibitor oligomycin-A greatly sensitized leukemia cells to TKI in vitro. Surprisingly, oligomycin-A sensitized leukemia cells to BCR-ABL inhibition at concentrations 100–1000-fold below those required for inhibition of respiration. Oligomycin-A treatment rapidly led to mitochondrial membrane depolarization and reduced ATP levels, and promoted superoxide production and leukemia cell apoptosis when combined with TKI. Importantly, oligomycin-A enhanced elimination of BCR-ABL+ leukemia cells by TKI in a mouse model and in primary blast crisis CML samples. Moreover, oligomycin-A also greatly potentiated the elimination of FLT3-dependent AML cells when combined with a FLT3 TKI, both in vitro and in vivo. TKI therapy in leukemia cells creates a novel metabolic state that is highly sensitive to particular mitochondrial perturbations. Targeting mitochondrial metabolism as an adjuvant therapy could therefore improve therapeutic responses to TKI for patients with BCR-ABL+ and FLT3ITD leukemias.