The deubiquitinase USP15 modulates cellular redox and is a therapeutic target in acute myeloid leukemia.
The deubiquitinase USP15 modulates cellular redox and is a therapeutic target in acute myeloid leukemia.
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DOI：
10.1038/s41375-021-01394-z
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发表时间：
2022-03
期刊：
影响因子：
11.4
通讯作者：
Starczynowski DT
中科院分区：
文献类型：
--
作者：
Niederkorn M;Ishikawa C;M Hueneman K;Bartram J;Stepanchick E;R Bennett J;E Culver-Cochran A;Bolanos LC;Uible E;Choi K;Wunderlich M;Perentesis JP;M Chlon T;Filippi MD;Starczynowski DT
泛素特异肽酶15(USP15)是一种脱泛素化酶，与细胞和肿瘤的发生密切相关。我们报道，与正常造血祖细胞相比，USP15在人类急性髓系白血病(AML)中过表达。USP15在AML中的高表达与Keap1蛋白和NRF2的抑制有关。在人和小鼠AML模型中，USP15的敲除或缺失显著损害白血病祖细胞的功能和生存能力，并通过Keap1-NRF2轴抑制抗氧化反应。抑制USP15和随后激活NRF2导致AML细胞的氧化还原扰动，这与白血病细胞功能受损是一致的。相比之下，在体外和体内，USP15对于人和小鼠正常的造血细胞是必不可少的。一种临床前的USP15小分子抑制剂诱导了Keap1-NRF2轴，损害了AML细胞的功能，提示靶向USP15的催化功能可以抑制AML。基于这些发现，我们报告了USP15通过抑制关键的氧化应激感受器机制和允许异常的氧化还原状态来部分地驱动AML细胞的功能。此外，我们假设，用小分子抑制剂抑制USP15活性将通过重新启动稳态氧化还原反应而选择性地损害白血病祖细胞，同时避免正常的造血。
Ubiquitin-specific peptidase 15 (USP15) is a deubiquitinating enzyme implicated in critical cellular and oncogenic processes. We report that USP15 mRNA and protein are overexpressed in human acute myeloid leukemia (AML) as compared to normal hematopoietic progenitor cells. This high expression of USP15 in AML correlates with KEAP1 protein and suppression of NRF2. Knockdown or deletion of USP15 in human and mouse AML models significantly impairs leukemic progenitor function and viability and de-represses an antioxidant response through the KEAP1-NRF2 axis. Inhibition of USP15 and subsequent activation of NRF2 leads to redox perturbations in AML cells, coincident with impaired leukemic cell function. In contrast, USP15 is dispensable for human and mouse normal hematopoietic cells in vitro and in vivo. A preclinical small-molecule inhibitor of USP15 induced the KEAP1-NRF2 axis and impaired AML cell function, suggesting that targeting USP15 catalytic function can suppress AML. Based on these findings, we report that USP15 drives AML cell function, in part, by suppressing a critical oxidative stress sensor mechanism and permitting an aberrant redox state. Furthermore, we postulate that inhibition of USP15 activity with small molecule inhibitors will selectively impair leukemic progenitor cells by re-engaging homeostatic redox responses while sparing normal hematopoiesis.
影响因子：
7
作者：
Wu YW;Lin CF;Lin YS;Su WC;Chiu WH
通讯作者：
Chiu WH