Department of Hematology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China.
Guangdong and Guangzhou Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, P. R. China.
Cell Death Dis. 2021 May 7;12(5):456. doi: 10.1038/s41419-021-03732-6.
Chronic myelogenous leukemia (CML) is a clonal malignancy of hematopoietic stem cells featured with the fusion protein kinase BCR-ABL. To elicit the mechanism underlying BCR-ABL stability, we perform a screen against a panel of deubiquitinating enzymes (DUBs) and find that the ubiquitin-specific protease 7 (USP7) drastically stabilizes the BCR-ABL fusion protein. Further studies show that USP7 interacts with BCR-ABL and blocks its polyubiquitination and degradation. Moreover, USP7 knockdown triggers BCR-ABL degradation and suppresses its downstream signaling transduction. In line with this finding, genetic or chemical inhibition of USP7 leads to BCR-ABL protein degradation, suppresses BCR/ABL signaling, and induces CML cell apoptosis. Furthermore, we find the antimalarial artesunate (ART) significantly inhibits USP7/BCR-ABL interaction, thereby promoting BCR-ABL degradation and inducing CML cell death. This study thus identifies USP7 as a putative Dub of BCR-ABL and provides a rationale in targeting USP7/BCR-ABL for the treatment of CML.
慢性髓性白血病（CML）是一种造血干细胞的克隆恶性肿瘤，其特征是融合蛋白激酶 BCR-ABL。为了阐明 BCR-ABL 稳定性的机制，我们对一组去泛素化酶（DUB）进行筛选，发现泛素特异性蛋白酶 7（USP7）可显著稳定 BCR-ABL 融合蛋白。进一步的研究表明，USP7 与 BCR-ABL 相互作用，阻止其多泛素化和降解。此外，USP7 的敲低会触发 BCR-ABL 降解并抑制其下游信号转导。与此发现一致，USP7 的遗传或化学抑制会导致 BCR-ABL 蛋白降解，抑制 BCR/ABL 信号，并诱导 CML 细胞凋亡。此外，我们发现抗疟药青蒿琥酯（ART）可显著抑制 USP7/BCR-ABL 相互作用，从而促进 BCR-ABL 降解并诱导 CML 细胞死亡。因此，本研究鉴定 USP7 为 BCR-ABL 的潜在 Dub，并为针对 USP7/BCR-ABL 治疗 CML 提供了一个合理的依据。
