Overcoming drug-resistance and the subsequent relapse that often occurs with monotherapy is crucial in the treatment of acute myeloid leukemia. We here demonstrate that therapy-resistant leukemia initiating cells can be targeted using a novel inhibitor of mitochondrial transcription (IMT). The compound inhibits mitochondrial RNA polymerase activity and sensitizes the resistant population to the induction of apoptosis. In vitro studies on acute myeloid leukemia cells demonstrate that IMT prevents cell proliferation, and together with a selective BCL-2 inhibitor, venetoclax, induces apoptosis and suppress oxidative phosphorylation (OXPHOS) synergistically. AML mouse models treated with IMT in combination with venetoclax show prolonged survival in venetoclax-resistant models. Our findings suggest that certain therapy-resistant leukemia cell populations display a unique dependency on mitochondrial transcription and can be targeted with IMT.

中文翻译：

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线粒体转录减少使急性髓系白血病细胞对 BCL-2 抑制敏感

克服单一疗法经常发生的耐药性和随后的复发对于急性髓系白血病的治疗至关重要。我们在此证明，可以使用一种新型线粒体转录抑制剂（IMT）来靶向治疗耐药性白血病起始细胞。该化合物抑制线粒体 RNA 聚合酶活性，并使耐药群体对细胞凋亡的诱导敏感。对急性髓性白血病细胞的体外研究表明，IMT 可防止细胞增殖，并与选择性 BCL-2 抑制剂 Venetoclax 一起协同诱导细胞凋亡并抑制氧化磷酸化 (OXPHOS)。用 IMT 联合 Venetoclax 治疗的 AML 小鼠模型显示 Venetoclax 耐药模型的生存期延长。我们的研究结果表明，某些耐药性白血病细胞群表现出对线粒体转录的独特依赖性，并且可以通过 IMT 来靶向。