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A conserved ZFX/WNT3 axis modulates the growth and imatinib response of chronic myeloid leukemia stem/progenitor cells
BACKGROUND: Zinc finger protein X-linked (ZFX) has been shown to promote the growth of tumor cells, including leukemic cells. However, the role of ZFX in the growth and drug response of chronic myeloid leukemia (CML) stem/progenitor cells remains unclear. METHODS: Real-time quantitative PCR (RT–qPCR...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10589942/ https://www.ncbi.nlm.nih.gov/pubmed/37864206 http://dx.doi.org/10.1186/s11658-023-00496-z |
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author | Zhang, Xiuyan Wang, Yu Lu, Jinchang Xiao, Lun Chen, Hui Li, Quanxue Li, Yuan-Yuan Xu, Peng Ruan, Changgeng Zhou, Haixia Zhao, Yun |
author_facet | Zhang, Xiuyan Wang, Yu Lu, Jinchang Xiao, Lun Chen, Hui Li, Quanxue Li, Yuan-Yuan Xu, Peng Ruan, Changgeng Zhou, Haixia Zhao, Yun |
author_sort | Zhang, Xiuyan |
collection | PubMed |
description | BACKGROUND: Zinc finger protein X-linked (ZFX) has been shown to promote the growth of tumor cells, including leukemic cells. However, the role of ZFX in the growth and drug response of chronic myeloid leukemia (CML) stem/progenitor cells remains unclear. METHODS: Real-time quantitative PCR (RT–qPCR) and immunofluorescence were used to analyze the expression of ZFX and WNT3 in CML CD34(+) cells compared with normal control cells. Short hairpin RNAs (shRNAs) and clustered regularly interspaced short palindromic repeats/dead CRISPR-associated protein 9 (CRISPR/dCas9) technologies were used to study the role of ZFX in growth and drug response of CML cells. Microarray data were generated to compare ZFX-silenced CML CD34(+) cells with their controls. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were performed to study the molecular mechanisms of ZFX to regulate WNT3 expression. RT–qPCR and western blotting were used to study the effect of ZFX on β-catenin signaling. RESULTS: We showed that ZFX expression was significantly higher in CML CD34(+) cells than in control cells. Overexpression and gene silencing experiments indicated that ZFX promoted the in vitro growth of CML cells, conferred imatinib mesylate (IM) resistance to these cells, and enhanced BCR/ABL-induced malignant transformation. Microarray data and subsequent validation revealed that WNT3 transcription was conservatively regulated by ZFX. WNT3 was highly expressed in CML CD34(+) cells, and WNT3 regulated the growth and IM response of these cells similarly to ZFX. Moreover, WNT3 overexpression partially rescued ZFX silencing-induced growth inhibition and IM hypersensitivity. ZFX silencing decreased WNT3/β-catenin signaling, including c-MYC and CCND1 expression. CONCLUSION: The present study identified a novel ZFX/WNT3 axis that modulates the growth and IM response of CML stem/progenitor cells. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s11658-023-00496-z. |
format | Online Article Text |
id | pubmed-10589942 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-105899422023-10-22 A conserved ZFX/WNT3 axis modulates the growth and imatinib response of chronic myeloid leukemia stem/progenitor cells Zhang, Xiuyan Wang, Yu Lu, Jinchang Xiao, Lun Chen, Hui Li, Quanxue Li, Yuan-Yuan Xu, Peng Ruan, Changgeng Zhou, Haixia Zhao, Yun Cell Mol Biol Lett Research BACKGROUND: Zinc finger protein X-linked (ZFX) has been shown to promote the growth of tumor cells, including leukemic cells. However, the role of ZFX in the growth and drug response of chronic myeloid leukemia (CML) stem/progenitor cells remains unclear. METHODS: Real-time quantitative PCR (RT–qPCR) and immunofluorescence were used to analyze the expression of ZFX and WNT3 in CML CD34(+) cells compared with normal control cells. Short hairpin RNAs (shRNAs) and clustered regularly interspaced short palindromic repeats/dead CRISPR-associated protein 9 (CRISPR/dCas9) technologies were used to study the role of ZFX in growth and drug response of CML cells. Microarray data were generated to compare ZFX-silenced CML CD34(+) cells with their controls. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were performed to study the molecular mechanisms of ZFX to regulate WNT3 expression. RT–qPCR and western blotting were used to study the effect of ZFX on β-catenin signaling. RESULTS: We showed that ZFX expression was significantly higher in CML CD34(+) cells than in control cells. Overexpression and gene silencing experiments indicated that ZFX promoted the in vitro growth of CML cells, conferred imatinib mesylate (IM) resistance to these cells, and enhanced BCR/ABL-induced malignant transformation. Microarray data and subsequent validation revealed that WNT3 transcription was conservatively regulated by ZFX. WNT3 was highly expressed in CML CD34(+) cells, and WNT3 regulated the growth and IM response of these cells similarly to ZFX. Moreover, WNT3 overexpression partially rescued ZFX silencing-induced growth inhibition and IM hypersensitivity. ZFX silencing decreased WNT3/β-catenin signaling, including c-MYC and CCND1 expression. CONCLUSION: The present study identified a novel ZFX/WNT3 axis that modulates the growth and IM response of CML stem/progenitor cells. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s11658-023-00496-z. BioMed Central 2023-10-20 /pmc/articles/PMC10589942/ /pubmed/37864206 http://dx.doi.org/10.1186/s11658-023-00496-z Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Zhang, Xiuyan Wang, Yu Lu, Jinchang Xiao, Lun Chen, Hui Li, Quanxue Li, Yuan-Yuan Xu, Peng Ruan, Changgeng Zhou, Haixia Zhao, Yun A conserved ZFX/WNT3 axis modulates the growth and imatinib response of chronic myeloid leukemia stem/progenitor cells |
title | A conserved ZFX/WNT3 axis modulates the growth and imatinib response of chronic myeloid leukemia stem/progenitor cells |
title_full | A conserved ZFX/WNT3 axis modulates the growth and imatinib response of chronic myeloid leukemia stem/progenitor cells |
title_fullStr | A conserved ZFX/WNT3 axis modulates the growth and imatinib response of chronic myeloid leukemia stem/progenitor cells |
title_full_unstemmed | A conserved ZFX/WNT3 axis modulates the growth and imatinib response of chronic myeloid leukemia stem/progenitor cells |
title_short | A conserved ZFX/WNT3 axis modulates the growth and imatinib response of chronic myeloid leukemia stem/progenitor cells |
title_sort | conserved zfx/wnt3 axis modulates the growth and imatinib response of chronic myeloid leukemia stem/progenitor cells |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10589942/ https://www.ncbi.nlm.nih.gov/pubmed/37864206 http://dx.doi.org/10.1186/s11658-023-00496-z |
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