USP10 modulates the SKP2/Bcr-Abl axis via stabilizing SKP2 in chronic myeloid leukemia
USP10 modulates the SKP2/Bcr-Abl axis via stabilizing SKP2 in chronic myeloid leukemia
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USP10 通过稳定慢性粒细胞白血病中的 SKP2 来调节 SKP2/Bcr-Abl 轴
DOI：
10.1038/s41421-019-0092-z
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发表时间：
2019-04-30
期刊：
影响因子：
33.5
通讯作者：
Liu, Jinbao
中科院分区：
文献类型：
--
作者：
Liao, Yuning;Liu, Ningning;Liu, Jinbao
酪氨酸激酶bcr-Abl的结构性激活是慢性粒细胞白血病(CML)发生发展的主要原因。目前，针对bcr-abl的酪氨酸激酶抑制剂(TKIs)的应用是CML患者的主要治疗方法。然而，在长期给药过程中，对TKI的获得性抵抗会导致TKI对晚期CML患者无效。因此，越来越多的研究集中在扩增表达或激活bcr-Abl，这被认为是促进晚期的研究。在这里，我们证明了S相激酶相关蛋白2(Skp2)通过介导K63连接的泛素化和激活而作为bcr-Abl的共同调节因子。进一步的研究表明，USP10作为Skp2的一种新的脱泛素酶，在CML细胞中通过介导Skp2的脱泛素化和稳定化来增强bcr-Abl的激活。此外，抑制USP10显著抑制对伊马替尼敏感和耐药的慢性粒细胞白血病细胞的增殖，这可能取决于Skp2状态。这一发现在原代CML细胞中得到证实，因为这些细胞过度表达USP10和Skp2，并且对USP10抑制剂敏感。综上所述，本研究不仅为CML中bcr-Abl的激活提供了一个新的视角，而且还证明了靶向USP10/Skp2/bcr-Abl轴是克服CML患者伊马替尼耐药的一种潜在策略。
Constitutive activation of tyrosine kinase Bcr-Abl is the leading cause of the development and progression of chronic myeloid leukemia (CML). Currently, the application of tyrosine kinase inhibitors (TKIs) targeting the Bcr-Abl is the primary therapy for CML patients. However, acquired resistance to TKIs that develops overtime in the long-term administration renders TKIs ineffective to patients with advanced CML. Therefore, increasing studies focus on the amplified expression or activation of Bcr-Abl which is proposed to contribute to the advanced phase. Here, we show that S-phase kinase-associated protein 2 (SKP2) acts as a co-regulator of Bcr-Abl by mediating its K63-linked ubiquitination and activation. Further investigations show that USP10 as a novel deubiquitinase of SKP2 amplifies the activation of Bcr-Abl via mediating deubiquitination and stabilization of SKP2 in CML cells. Moreover, inhibition of USP10 significantly suppresses the proliferation of both imatinib-sensitive and imatinib-resistant CML cells, which likely depends on SKP2 status. This findings are confirmed in primary CML cells because these cells are over-expressed with USP10 and SKP2 and are sensitive to a USP10 inhibitor. Taken together, the present study not only provides a novel insight into the amplified activation of Bcr-Abl in CML, but also demonstrates that targeting the USP10/SKP2/Bcr-Abl axis is a potential strategy to overcome imatinib resistance in CML patients.