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Targeting USP47 overcomes tyrosine kinase inhibitor resistance and eradicates leukemia stem/progenitor cells in chronic myelogenous leukemia
Identifying novel drug targets to overcome resistance to tyrosine kinase inhibitors (TKIs) and eradicating leukemia stem/progenitor cells are required for the treatment of chronic myelogenous leukemia (CML). Here, we show that ubiquitin-specific peptidase 47 (USP47) is a potential target to overcome...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782553/ https://www.ncbi.nlm.nih.gov/pubmed/33397955 http://dx.doi.org/10.1038/s41467-020-20259-0 |
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author | Lei, Hu Xu, Han-Zhang Shan, Hui-Zhuang Liu, Meng Lu, Ying Fang, Zhi-Xiao Jin, Jin Jing, Bo Xiao, Xin-Hua Gao, Shen-Meng Gao, Feng-Hou Xia, Li Yang, Li Liu, Li-Gen Wang, Wei-Wei Liu, Chuan-Xu Tong, Yin Wu, Yun-Zhao Zheng, Jun-Ke Chen, Guo-Qiang Zhou, Li Wu, Ying-Li |
author_facet | Lei, Hu Xu, Han-Zhang Shan, Hui-Zhuang Liu, Meng Lu, Ying Fang, Zhi-Xiao Jin, Jin Jing, Bo Xiao, Xin-Hua Gao, Shen-Meng Gao, Feng-Hou Xia, Li Yang, Li Liu, Li-Gen Wang, Wei-Wei Liu, Chuan-Xu Tong, Yin Wu, Yun-Zhao Zheng, Jun-Ke Chen, Guo-Qiang Zhou, Li Wu, Ying-Li |
author_sort | Lei, Hu |
collection | PubMed |
description | Identifying novel drug targets to overcome resistance to tyrosine kinase inhibitors (TKIs) and eradicating leukemia stem/progenitor cells are required for the treatment of chronic myelogenous leukemia (CML). Here, we show that ubiquitin-specific peptidase 47 (USP47) is a potential target to overcome TKI resistance. Functional analysis shows that USP47 knockdown represses proliferation of CML cells sensitive or resistant to imatinib in vitro and in vivo. The knockout of Usp47 significantly inhibits BCR-ABL and BCR-ABL(T315I)-induced CML in mice with the reduction of Lin(−)Sca1(+)c-Kit(+) CML stem/progenitor cells. Mechanistic studies show that stabilizing Y-box binding protein 1 contributes to USP47-mediated DNA damage repair in CML cells. Inhibiting USP47 by P22077 exerts cytotoxicity to CML cells with or without TKI resistance in vitro and in vivo. Moreover, P22077 eliminates leukemia stem/progenitor cells in CML mice. Together, targeting USP47 is a promising strategy to overcome TKI resistance and eradicate leukemia stem/progenitor cells in CML. |
format | Online Article Text |
id | pubmed-7782553 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-77825532021-01-11 Targeting USP47 overcomes tyrosine kinase inhibitor resistance and eradicates leukemia stem/progenitor cells in chronic myelogenous leukemia Lei, Hu Xu, Han-Zhang Shan, Hui-Zhuang Liu, Meng Lu, Ying Fang, Zhi-Xiao Jin, Jin Jing, Bo Xiao, Xin-Hua Gao, Shen-Meng Gao, Feng-Hou Xia, Li Yang, Li Liu, Li-Gen Wang, Wei-Wei Liu, Chuan-Xu Tong, Yin Wu, Yun-Zhao Zheng, Jun-Ke Chen, Guo-Qiang Zhou, Li Wu, Ying-Li Nat Commun Article Identifying novel drug targets to overcome resistance to tyrosine kinase inhibitors (TKIs) and eradicating leukemia stem/progenitor cells are required for the treatment of chronic myelogenous leukemia (CML). Here, we show that ubiquitin-specific peptidase 47 (USP47) is a potential target to overcome TKI resistance. Functional analysis shows that USP47 knockdown represses proliferation of CML cells sensitive or resistant to imatinib in vitro and in vivo. The knockout of Usp47 significantly inhibits BCR-ABL and BCR-ABL(T315I)-induced CML in mice with the reduction of Lin(−)Sca1(+)c-Kit(+) CML stem/progenitor cells. Mechanistic studies show that stabilizing Y-box binding protein 1 contributes to USP47-mediated DNA damage repair in CML cells. Inhibiting USP47 by P22077 exerts cytotoxicity to CML cells with or without TKI resistance in vitro and in vivo. Moreover, P22077 eliminates leukemia stem/progenitor cells in CML mice. Together, targeting USP47 is a promising strategy to overcome TKI resistance and eradicate leukemia stem/progenitor cells in CML. Nature Publishing Group UK 2021-01-04 /pmc/articles/PMC7782553/ /pubmed/33397955 http://dx.doi.org/10.1038/s41467-020-20259-0 Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Lei, Hu Xu, Han-Zhang Shan, Hui-Zhuang Liu, Meng Lu, Ying Fang, Zhi-Xiao Jin, Jin Jing, Bo Xiao, Xin-Hua Gao, Shen-Meng Gao, Feng-Hou Xia, Li Yang, Li Liu, Li-Gen Wang, Wei-Wei Liu, Chuan-Xu Tong, Yin Wu, Yun-Zhao Zheng, Jun-Ke Chen, Guo-Qiang Zhou, Li Wu, Ying-Li Targeting USP47 overcomes tyrosine kinase inhibitor resistance and eradicates leukemia stem/progenitor cells in chronic myelogenous leukemia |
title | Targeting USP47 overcomes tyrosine kinase inhibitor resistance and eradicates leukemia stem/progenitor cells in chronic myelogenous leukemia |
title_full | Targeting USP47 overcomes tyrosine kinase inhibitor resistance and eradicates leukemia stem/progenitor cells in chronic myelogenous leukemia |
title_fullStr | Targeting USP47 overcomes tyrosine kinase inhibitor resistance and eradicates leukemia stem/progenitor cells in chronic myelogenous leukemia |
title_full_unstemmed | Targeting USP47 overcomes tyrosine kinase inhibitor resistance and eradicates leukemia stem/progenitor cells in chronic myelogenous leukemia |
title_short | Targeting USP47 overcomes tyrosine kinase inhibitor resistance and eradicates leukemia stem/progenitor cells in chronic myelogenous leukemia |
title_sort | targeting usp47 overcomes tyrosine kinase inhibitor resistance and eradicates leukemia stem/progenitor cells in chronic myelogenous leukemia |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782553/ https://www.ncbi.nlm.nih.gov/pubmed/33397955 http://dx.doi.org/10.1038/s41467-020-20259-0 |
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