Inhibition of USP1 reverses the chemotherapy resistance through destabilization of MAX in the relapsed/refractory B-cell lymphoma
© 2022. The Author(s)..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:37 |
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| Enthalten in: |
Leukemia - 37(2023), 1 vom: 09. Jan., Seite 164-177 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Li, Xi-Ya [VerfasserIn] |
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| Links: |
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| Themen: |
1HIZ4DL86F |
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| Anmerkungen: |
Date Completed 31.01.2023 Date Revised 14.02.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41375-022-01747-2 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM348658087 |
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| 100 | 1 | |a Li, Xi-Ya |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Inhibition of USP1 reverses the chemotherapy resistance through destabilization of MAX in the relapsed/refractory B-cell lymphoma |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
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| 500 | |a Date Completed 31.01.2023 | ||
| 500 | |a Date Revised 14.02.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022. The Author(s). | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Rituximab |2 NLM | |
| 650 | 7 | |a 4F4X42SYQ6 |2 NLM | |
| 650 | 7 | |a Pimozide |2 NLM | |
| 650 | 7 | |a 1HIZ4DL86F |2 NLM | |
| 650 | 7 | |a Ubiquitin-Specific Proteases |2 NLM | |
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| 700 | 1 | |a Wu, Ji-Chuan |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Ping |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Zi-Juan |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yong |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Bing-Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Cheng-Long |e verfasserin |4 aut | |
| 700 | 1 | |a Fei, Ming-Yue |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Peng-Cheng |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Yi-Lun |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Chun-Hui |e verfasserin |4 aut | |
| 700 | 1 | |a Chang, Bin-He |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Xin-Chi |e verfasserin |4 aut | |
| 700 | 1 | |a Zong, Li-Juan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Jia-Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Fang, Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Xiao-Jian |e verfasserin |4 aut | |
| 700 | 1 | |a Xue, Kai |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Li |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Shu-Bei |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Shi-Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Gui, Ai-Ling |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Ling |e verfasserin |4 aut | |
| 700 | 1 | |a Gu, Juan J |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Bao-Hua |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Qun-Ling |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Lan |e verfasserin |4 aut | |
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