Inhibition of autophagy has been proposed as a potential therapy for individuals with cancer. However, current lysosomotropic autophagy inhibitors have demonstrated limited efficacy in clinical trials. Therefore, validation of novel specific autophagy inhibitors using robust preclinical models is critical. In chronic myeloid leukemia (CML), minimal residual disease is maintained by persistent leukemic stem cells (LSCs), which drive tyrosine kinase inhibitor (TKI) resistance and patient relapse. Here, we show that deletion of autophagy-inducing kinase ULK1 (unc-51–like autophagy activating kinase 1) reduces growth of cell line and patient-derived xenografted CML cells in mouse models. Using primitive cells, isolated from individuals with CML, we demonstrate that pharmacological inhibition of ULK1 selectively targets CML LSCs ex vivo and in vivo, when combined with TKI treatment. The enhanced TKI sensitivity after ULK1-mediated autophagy inhibition is driven by increased mitochondrial respiration and loss of quiescence and points to oxidative stress–induced differentiation of CML LSCs, proposing an alternative strategy for treating patients with CML.

中文翻译：

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ULK1 抑制促进氧化应激诱导的分化并使白血病干细胞对靶向治疗敏感


抑制自噬已被提议作为癌症个体的潜在疗法。然而，目前的溶酶体自噬抑制剂在临床试验中已证明疗效有限。因此，使用稳健的临床前模型验证新型特异性自噬抑制剂至关重要。在慢性粒细胞白血病 (CML) 中，微小残留病由持续性白血病干细胞 (LSC) 维持，从而导致酪氨酸激酶抑制剂 (TKI) 耐药和患者复发。在这里，我们发现，自噬诱导激酶 ULK1（unc-51 样自噬激活激酶 1）的缺失会降低小鼠模型中细胞系和患者来源的异种移植 CML 细胞的生长。使用从患有 CML 的个体中分离出的原始细胞，我们证明，当与 TKI 治疗相结合时，ULK1 的药理抑制选择性地在体外和体内靶向 CML LSC。 ULK1 介导的自噬抑制后 TKI 敏感性增强，这是由线粒体呼吸增加和静止状态丧失驱动的，表明氧化应激诱导 CML LSC 分化，为治疗 CML 患者提出了另一种策略。