Lu Xinxin, Huang Xinyue, Xu Haiqi, Lu Saien, You Shilong, Xu Jiaqi, Zhan Qianru, Dong Chao, Zhang Ning, Zhang Ying, Cao Liu, Zhang Xingang, Zhang Naijin, Zhang Lijun
Department of Hematology, the First Hospital of China Medical University, Shenyang, Liaoning, China.
Department of Cardiology, the First Hospital of China Medical University, Shenyang, Liaoning, China.
Cell Death Discov. 2022 Oct 18;8(1):421. doi: 10.1038/s41420-022-01209-9.
Acute lymphoblastic leukemia (ALL) has been a huge threat for people's health and finding effective target therapy is urgent and important. WWP2, as one of E3 ubiquitin ligase, is involved in many biological processes by specifically binding to substrates. PARP1 plays a role in cell apoptosis and is considered as a therapeutic target of certain cancers. In this study, we firstly found that WWP2 expressed higher in newly diagnosed ALL patients comparing with complete remission (CR) ALL patients and normal control people, and WWP2 in relapse ALL patients expressed higher than normal control people. WWP2 expression was related with the FAB subtype of ALL and the proportion of blast cells in bone marrow blood tested by flow cytometry. We demonstrated knockout WWP2 inhibited the ALL growth and enhanced apoptosis induced by Dox in vitro and vivo for the first time. WWP2 negatively regulated and interacted with PARP1 and WWP2 mechanically degraded PARP1 through polyubiquitin-proteasome pathway in ALL. These findings suggested WWP2 played a role in ALL development as well as growth and apoptosis, and also displayed a regulatory pathway of PARP1, which provided a new potential therapeutic target for the treatment of ALL.
急性淋巴细胞白血病（ALL）一直是对人类健康的巨大威胁，寻找有效的靶向治疗方法迫在眉睫且至关重要。WWP2作为E3泛素连接酶之一，通过特异性结合底物参与许多生物学过程。PARP1在细胞凋亡中起作用，被认为是某些癌症的治疗靶点。在本研究中，我们首先发现，与完全缓解（CR）的ALL患者及正常对照人群相比，初诊ALL患者中WWP2表达更高，而复发ALL患者中WWP2的表达高于正常对照人群。WWP2表达与ALL的FAB亚型以及通过流式细胞术检测的骨髓血中原始细胞比例相关。我们首次证明敲除WWP2在体外和体内均能抑制ALL生长并增强阿霉素诱导的细胞凋亡。在ALL中，WWP2通过多聚泛素 - 蛋白酶体途径对PARP1进行负调控并与之相互作用，且WWP2可机械性降解PARP1。这些发现表明WWP2在ALL的发生发展以及生长和凋亡过程中发挥作用，同时也展示了PARP1的一条调控途径，这为ALL的治疗提供了一个新的潜在治疗靶点。
