Inhibition of USP1 reverses the chemotherapy resistance through destabilization of MAX in the relapsed/refractory B-cell lymphoma

• DOI: 10.1038/s41375-022-01747-2
• Publication Date: 2022-11-09T10:03:09Z
• Authors: Xi-Ya Li; Ji-Chuan Wu; Ping Liu; Zi-Juan Li; Yong Wang; Bing-Yi Chen; Cheng-Long Hu; Ming-Yue Fei; Peng-Cheng Yu; Yi-Lun Jiang; Chun-Hui Xu; Bin-He Chang; Xin-Chi Chen; Li-Juan Zong; Jia-Ying Zhang; Ying Fang; Xiao-Jian Sun; Kai Xue; Li Wang; Shu-Bei Chen; Shi-Yu Jiang; Ai-ling Gui; Ling Yang; Juan J. Gu; Bao-Hua Yu; Qun-ling Zhang; Lan Wang
• Keywords: 0303 health sciences; Lymphoma, Non-Hodgkin; Pimozide; Article; 3. Good health; Mice; 03 medical and health sciences; Antineoplastic Combined Chemotherapy Protocols; Animals; Humans; Lymphoma, Large B-Cell, Diffuse; Ubiquitin-Specific Proteases; Rituximab

AbstractThe patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL) have poor prognosis, and a novel and effective therapeutic strategy for these patients is urgently needed. Although ubiquitin-specific protease 1 (USP1) plays a key role in cancer, the carcinogenic effect of USP1 in B-cell lymphoma remains elusive. Here we found that USP1 is highly expressed in DLBCL patients, and high expression of USP1 predicts poor prognosis. Knocking down USP1 or a specific inhibitor of USP1, pimozide, induced cell growth inhibition, cell cycle arrest and autophagy in DLBCL cells. Targeting USP1 by shRNA or pimozide significantly reduced tumor burden of a mouse model established with engraftment of rituximab/chemotherapy resistant DLBCL cells. Pimozide significantly retarded the growth of lymphoma in a DLBCL patient-derived xenograft (PDX) model. USP1 directly interacted with MAX, a MYC binding protein, and maintained the stability of MAX through deubiquitination, which promoted the transcription of MYC target genes. Moreover, pimozide showed a synergetic effect with etoposide, a chemotherapy drug, in cell and mouse models of rituximab/chemotherapy resistant DLBCL. Our study highlights the critical role of USP1 in the rituximab/chemotherapy resistance of DLBCL through deubiquitylating MAX, and provides a novel therapeutic strategy for rituximab/chemotherapy resistant DLBCL.