Journal
LEUKEMIA
Volume 37, Issue 1, Pages 164-177Publisher
SPRINGERNATURE
DOI: 10.1038/s41375-022-01747-2
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This study found that high expression of ubiquitin-specific protease 1 (USP1) is correlated with poor prognosis in patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL). Knocking down or inhibiting USP1 can suppress cell growth, induce cell cycle arrest, and promote autophagy in DLBCL cells. Targeting USP1 can significantly reduce tumor burden in mouse and patient-derived xenograft (PDX) models of DLBCL. USP1 interacts with the MYC binding protein MAX and maintains its stability through deubiquitination, which promotes the transcription of MYC target genes. Additionally, the drug pimozide shows synergistic effects with the chemotherapy drug etoposide in models of rituximab/chemotherapy resistant DLBCL.
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.
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