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HIF-PH Encoded by EGLN1 Is a Potential Therapeutic Target for Chronic Lymphocytic Leukemia

Owing to the recent emergence of drug resistance to Bruton’s tyrosine kinase inhibitors (BTK) in chronic lymphocytic leukemia (CLL) treatment, it is crucial to identify alternative therapeutic targets. Therefore, we aimed to identify therapeutic options for CLL besides BTK. We identified that HIF1A...

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Autores principales: Guo, Wancheng, Liang, Daomiao, Wang, Peilong, Yin, Le, Zhang, Huifang, Xing, Cheng, Huang, Zineng, Wu, Yinghua, Li, Heng, Cheng, Zhao, Xiao, Xiaojuan, Liu, Jing, Wang, Zhihua, Peng, Hongling
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9229586/
https://www.ncbi.nlm.nih.gov/pubmed/35745653
http://dx.doi.org/10.3390/ph15060734
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author Guo, Wancheng
Liang, Daomiao
Wang, Peilong
Yin, Le
Zhang, Huifang
Xing, Cheng
Huang, Zineng
Wu, Yinghua
Li, Heng
Cheng, Zhao
Xiao, Xiaojuan
Liu, Jing
Wang, Zhihua
Peng, Hongling
author_facet Guo, Wancheng
Liang, Daomiao
Wang, Peilong
Yin, Le
Zhang, Huifang
Xing, Cheng
Huang, Zineng
Wu, Yinghua
Li, Heng
Cheng, Zhao
Xiao, Xiaojuan
Liu, Jing
Wang, Zhihua
Peng, Hongling
author_sort Guo, Wancheng
collection PubMed
description Owing to the recent emergence of drug resistance to Bruton’s tyrosine kinase inhibitors (BTK) in chronic lymphocytic leukemia (CLL) treatment, it is crucial to identify alternative therapeutic targets. Therefore, we aimed to identify therapeutic options for CLL besides BTK. We identified that HIF1A expression was higher in CLL patients than in controls, which may suggest good prognosis. We used a lentiviral knockdown of EGLN1 (encoding hypoxia-inducible factor prolyl hydroxylase [HIF-PH]) and found that the growth of MEC-1 cells slowed in the knockdown group. Treatment of CLL cell lines MEC-1 and HG3 with the HIF-PH inhibitor molidustat showed that molidustat could induce apoptosis in a concentration-dependent manner in CLL cells and had low cytotoxicity at this concentration. CXCR4, HIF1A, SLC2AI, and VEGF, the downstream molecules of the HIF pathway, were upregulated after molidustat treatment. Western blotting results indicated that molidustat increased HIF1A expression in CLL cell lines and cells from CLL patients, and sequencing/quantitative PCR analysis demonstrated that the ribosome biogenesis pathway was inhibited in MEC-1 cells after molidustat treatment. We further identified synergistic cytotoxicity of molidustat in combination with ibrutinib on the MEC-1 and HG3 cell lines at certain concentrations. Therefore, molidustat is a potential therapeutic option for CLL.
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spelling pubmed-92295862022-06-25 HIF-PH Encoded by EGLN1 Is a Potential Therapeutic Target for Chronic Lymphocytic Leukemia Guo, Wancheng Liang, Daomiao Wang, Peilong Yin, Le Zhang, Huifang Xing, Cheng Huang, Zineng Wu, Yinghua Li, Heng Cheng, Zhao Xiao, Xiaojuan Liu, Jing Wang, Zhihua Peng, Hongling Pharmaceuticals (Basel) Article Owing to the recent emergence of drug resistance to Bruton’s tyrosine kinase inhibitors (BTK) in chronic lymphocytic leukemia (CLL) treatment, it is crucial to identify alternative therapeutic targets. Therefore, we aimed to identify therapeutic options for CLL besides BTK. We identified that HIF1A expression was higher in CLL patients than in controls, which may suggest good prognosis. We used a lentiviral knockdown of EGLN1 (encoding hypoxia-inducible factor prolyl hydroxylase [HIF-PH]) and found that the growth of MEC-1 cells slowed in the knockdown group. Treatment of CLL cell lines MEC-1 and HG3 with the HIF-PH inhibitor molidustat showed that molidustat could induce apoptosis in a concentration-dependent manner in CLL cells and had low cytotoxicity at this concentration. CXCR4, HIF1A, SLC2AI, and VEGF, the downstream molecules of the HIF pathway, were upregulated after molidustat treatment. Western blotting results indicated that molidustat increased HIF1A expression in CLL cell lines and cells from CLL patients, and sequencing/quantitative PCR analysis demonstrated that the ribosome biogenesis pathway was inhibited in MEC-1 cells after molidustat treatment. We further identified synergistic cytotoxicity of molidustat in combination with ibrutinib on the MEC-1 and HG3 cell lines at certain concentrations. Therefore, molidustat is a potential therapeutic option for CLL. MDPI 2022-06-10 /pmc/articles/PMC9229586/ /pubmed/35745653 http://dx.doi.org/10.3390/ph15060734 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Guo, Wancheng
Liang, Daomiao
Wang, Peilong
Yin, Le
Zhang, Huifang
Xing, Cheng
Huang, Zineng
Wu, Yinghua
Li, Heng
Cheng, Zhao
Xiao, Xiaojuan
Liu, Jing
Wang, Zhihua
Peng, Hongling
HIF-PH Encoded by EGLN1 Is a Potential Therapeutic Target for Chronic Lymphocytic Leukemia
title HIF-PH Encoded by EGLN1 Is a Potential Therapeutic Target for Chronic Lymphocytic Leukemia
title_full HIF-PH Encoded by EGLN1 Is a Potential Therapeutic Target for Chronic Lymphocytic Leukemia
title_fullStr HIF-PH Encoded by EGLN1 Is a Potential Therapeutic Target for Chronic Lymphocytic Leukemia
title_full_unstemmed HIF-PH Encoded by EGLN1 Is a Potential Therapeutic Target for Chronic Lymphocytic Leukemia
title_short HIF-PH Encoded by EGLN1 Is a Potential Therapeutic Target for Chronic Lymphocytic Leukemia
title_sort hif-ph encoded by egln1 is a potential therapeutic target for chronic lymphocytic leukemia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9229586/
https://www.ncbi.nlm.nih.gov/pubmed/35745653
http://dx.doi.org/10.3390/ph15060734
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