The Wang Lan research group of the Institute of Nutrition and Health cooperated to reveal the mechanism of USP1 regulation of relapsed and refractory B-cell lymphoma

In this study, the researchers found that ubiquitin-specific protease 1 (USP1) is highly expressed in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), and that high USP1 expression is significantly associated with poor prognosis in patients with
DLBCL.
In this study, USP1 deletion significantly inhibited the proliferation of DLBCL cells, induced cell cycle arrest, and activated autophagy, and knocked down USP1 in DLBCL cells in DLBCL mouse transplanted tumor models significantly inhibited the growth
of nude mouse lymphoma.
Subsequently, in terms of mechanism, the researchers found that USP1 interacts with MAX to maintain the stability of MAX/MYC heterodimer through deubiquitination modifications, thereby regulating the transcription
of MYC target genes.

In order to study the targeted therapeutic effect of USP1 in DLBCL, the researchers used the USP1-specific inhibitor pimozide for experiments, and found that pimozide can significantly inhibit DLBCL cell proliferation, induce cell cycle arrest, increase autophagy, and pimozide treatment can also significantly hinder tumor proliferation
in DLBCL cells or tumor xenograft mouse models of patients.
In addition, pimozide has a synergistic effect with chemotherapy drugs such as etoposide both in vitro and in vivo
.
In summary, the study reveals the key role of USP1 in rituximab/chemo-resistant DLBCL, and the USP1 inhibitor pimozide may have important guiding significance
for the treatment of clinical rituximab/chemoresistant DLBCL.

Wang Lan, researcher at Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, and Zhang Qunling, chief physician of the Department of Medical Oncology, Fudan University Cancer Hospital, are the co-corresponding authors of the paper, and Li Xia, a doctoral student at the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Wu Jibian and Liu Ping, a doctoral student, are the first authors
of the paper.
This work has been strongly supported by several medical and scientific collaborators, including Professor Gu Jun of Roswell Park Cancer Institute, and Chief Physician
Wang Li of Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine.
This project has been funded by the National Natural Science Foundation of China, the Ministry of Science and Technology, the Shanghai Municipal Science and Technology Innovation Action Plan, and the Chinese Academy of Sciences
.

Fig.
Schematic diagram of the molecular mechanism by which USP1 regulates DLBCL