A mitophagy inhibitor targeting p62 attenuates the leukemia-initiation potential of acute myeloid leukemia cells
A mitophagy inhibitor targeting p62 attenuates the leukemia-initiation potential of acute myeloid leukemia cells
复制标题
一种针对 p62 的线粒体自噬抑制剂可减弱急性髓系白血病细胞的白血病启动潜力
DOI：
10.1016/j.canlet.2021.04.003
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发表时间：
2021-04-18
期刊：
影响因子：
9.7
通讯作者：
Gao, Yingdai
中科院分区：
文献类型：
--
作者：
Li, Yinghui;Li, Yafang;Gao, Yingdai
急性髓系白血病（AML）中白血病起始细胞（LIC）的致瘤潜力越来越受到关注。尽管选择性自噬在造血干细胞（HSC）的终身维持、癌症进展和化疗耐药性中起着重要作用，但LIC与选择性自噬之间的关系仍有待充分阐明。Sequestosome 1（SQSTM 1），也称为p62，是一种选择性自噬受体，用于降解泛素化底物，其丢失会损害AML小鼠模型中的白血病进展。在这项研究中，我们评估了线粒体自噬与XRK 3F 2（一种p62-ZZ抑制剂）在LIC存活中的潜在机制。我们证明，XRK 3F 2选择性地损害LIC，但在小鼠和患者来源的肿瘤异种移植物（PDX）AML模型中保留正常HSC。在机制上，我们观察到XRK 3F 2通过抑制p62与缺陷线粒体的结合来阻断线粒体自噬。我们的研究不仅评估了XRK 3F 2在LIC中的有效性和安全性，而且还证明了线粒体自噬在AML发展和进展期间对LIC的生存起着不可或缺的作用，这可以通过阻断p62来削弱。
There has been an increasing focus on the tumorigenic potential of leukemia initiating cells (LICs) in acute myeloid leukemia (AML). Despite the important role of selective autophagy in the life-long maintenance of hematopoietic stem cells (HSCs), cancer progression, and chemoresistance, the relationship between LICs and selective autophagy remains to be fully elucidated. Sequestosome 1 (SQSTM1), also known as p62, is a selective autophagy receptor for the degradation of ubiquitinated substrates, and its loss impairs leukemia progression in AML mouse models. In this study, we evaluated the underlying mechanisms of mitophagy in the survival of LICs with XRK3F2, a p62-ZZ inhibitor. We demonstrated that XRK3F2 selectively impaired LICs but spared normal HSCs in both mouse and patient-derived tumor xenograft (PDX) AML models. Mechanistically, we observed that XRK3F2 blocked mitophagy by inhibiting the binding of p62 with defective mitochondria. Our study not only evaluated the effectiveness and safety of XRK3F2 in LICs, but also demonstrated that mitophagy plays an indispensable role in the survival of LICs during AML development and progression, which can be impaired by blocking p62.