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

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

The 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-ce...

Full description

Saved in:

Bibliographic Details
Published in:	Leukemia 2023-01, Vol.37 (1), p.164-177
Main Authors:	Li, Xi-Ya, Wu, Ji-Chuan, Liu, Ping, Li, Zi-Juan, Wang, Yong, Chen, Bing-Yi, Hu, Cheng-Long, Fei, Ming-Yue, Yu, Peng-Cheng, Jiang, Yi-Lun, Xu, Chun-Hui, Chang, Bin-He, Chen, Xin-Chi, Zong, Li-Juan, Zhang, Jia-Ying, Fang, Ying, Sun, Xiao-Jian, Xue, Kai, Wang, Li, Chen, Shu-Bei, Jiang, Shi-Yu, Gui, Ai-Ling, Yang, Ling, Gu, Juan J, Yu, Bao-Hua, Zhang, Qun-Ling, Wang, Lan
Format:	Article
Language:	eng
Subjects:	Animals Antineoplastic Combined Chemotherapy Protocols - therapeutic use Humans Lymphoma, Large B-Cell, Diffuse - drug therapy Lymphoma, Large B-Cell, Diffuse - genetics Lymphoma, Large B-Cell, Diffuse - pathology Lymphoma, Non-Hodgkin - drug therapy Mice Pimozide - therapeutic use Rituximab - therapeutic use Ubiquitin-Specific Proteases - genetics
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	The 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.
ISSN:	0887-6924 1476-5551