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Depletion of γ-catenin by Histone Deacetylase Inhibition Confers Elimination of CML Stem Cells in Combination with Imatinib
Quiescent leukemia stem cells (LSCs) that are insensitive to BCR-ABL tyrosine kinase inhibitors confer resistance to imatinib in chronic myelogenous leukemia (CML). Identifying proteins to regulate survival and stemness of LSCs is urgently needed. Although histone deacetylase inhibitors (HDACis) can...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4997248/ https://www.ncbi.nlm.nih.gov/pubmed/27570562 http://dx.doi.org/10.7150/thno.16139 |
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author | Jin, Yanli Yao, Yiwu Chen, Li Zhu, Xiaohui Jin, Bei Shen, Yingying Li, Juan Du, Xin Lu, Yuhong Jiang, Sheng Pan, Jingxuan |
author_facet | Jin, Yanli Yao, Yiwu Chen, Li Zhu, Xiaohui Jin, Bei Shen, Yingying Li, Juan Du, Xin Lu, Yuhong Jiang, Sheng Pan, Jingxuan |
author_sort | Jin, Yanli |
collection | PubMed |
description | Quiescent leukemia stem cells (LSCs) that are insensitive to BCR-ABL tyrosine kinase inhibitors confer resistance to imatinib in chronic myelogenous leukemia (CML). Identifying proteins to regulate survival and stemness of LSCs is urgently needed. Although histone deacetylase inhibitors (HDACis) can eliminate quiescent LSCs in CML, little is known about the underlying mechanism that HDACis kill LSCs. By fishing with a biotin-labeled probe, we identified that HDACi JSL-1 bound to the protein γ-catenin. γ-Catenin expression was higher in LSCs from CML patients than normal hematopoietic stem cells. Silencing γ-catenin in human CML CD34(+) bone-marrow (BM) cells sufficiently eliminated LSCs, which suggests that γ-catenin is required for survival of CML LSCs. Pharmacological inhibition of γ-catenin thwarted survival and self-renewal of human CML CD34(+) cells in vitro, and of murine LSCs in BCR-ABL-driven CML mice. γ-Catenin inhibition reduced long-term engraftment of human CML CD34(+) cells in NOD.Cg-Prkdc(scid) II2rg(tm1Sug)/JicCrl (NOG) mice. Silencing γ-catenin by shRNA in human primary CD34(+) cells did not alter β-catenin, implying a β-catenin-independent role of γ-catenin in survival and self-renewal of CML LSCs. Taken together, our findings validate that γ-catenin may be a novel therapeutic target of LSCs, and suppression of γ-catenin by HDACi may explain elimination of CML LSCs. |
format | Online Article Text |
id | pubmed-4997248 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
spelling | pubmed-49972482016-08-26 Depletion of γ-catenin by Histone Deacetylase Inhibition Confers Elimination of CML Stem Cells in Combination with Imatinib Jin, Yanli Yao, Yiwu Chen, Li Zhu, Xiaohui Jin, Bei Shen, Yingying Li, Juan Du, Xin Lu, Yuhong Jiang, Sheng Pan, Jingxuan Theranostics Research Paper Quiescent leukemia stem cells (LSCs) that are insensitive to BCR-ABL tyrosine kinase inhibitors confer resistance to imatinib in chronic myelogenous leukemia (CML). Identifying proteins to regulate survival and stemness of LSCs is urgently needed. Although histone deacetylase inhibitors (HDACis) can eliminate quiescent LSCs in CML, little is known about the underlying mechanism that HDACis kill LSCs. By fishing with a biotin-labeled probe, we identified that HDACi JSL-1 bound to the protein γ-catenin. γ-Catenin expression was higher in LSCs from CML patients than normal hematopoietic stem cells. Silencing γ-catenin in human CML CD34(+) bone-marrow (BM) cells sufficiently eliminated LSCs, which suggests that γ-catenin is required for survival of CML LSCs. Pharmacological inhibition of γ-catenin thwarted survival and self-renewal of human CML CD34(+) cells in vitro, and of murine LSCs in BCR-ABL-driven CML mice. γ-Catenin inhibition reduced long-term engraftment of human CML CD34(+) cells in NOD.Cg-Prkdc(scid) II2rg(tm1Sug)/JicCrl (NOG) mice. Silencing γ-catenin by shRNA in human primary CD34(+) cells did not alter β-catenin, implying a β-catenin-independent role of γ-catenin in survival and self-renewal of CML LSCs. Taken together, our findings validate that γ-catenin may be a novel therapeutic target of LSCs, and suppression of γ-catenin by HDACi may explain elimination of CML LSCs. Ivyspring International Publisher 2016-08-12 /pmc/articles/PMC4997248/ /pubmed/27570562 http://dx.doi.org/10.7150/thno.16139 Text en © Ivyspring International Publisher. Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited. See http://ivyspring.com/terms for terms and conditions. |
spellingShingle | Research Paper Jin, Yanli Yao, Yiwu Chen, Li Zhu, Xiaohui Jin, Bei Shen, Yingying Li, Juan Du, Xin Lu, Yuhong Jiang, Sheng Pan, Jingxuan Depletion of γ-catenin by Histone Deacetylase Inhibition Confers Elimination of CML Stem Cells in Combination with Imatinib |
title | Depletion of γ-catenin by Histone Deacetylase Inhibition Confers Elimination of CML Stem Cells in Combination with Imatinib |
title_full | Depletion of γ-catenin by Histone Deacetylase Inhibition Confers Elimination of CML Stem Cells in Combination with Imatinib |
title_fullStr | Depletion of γ-catenin by Histone Deacetylase Inhibition Confers Elimination of CML Stem Cells in Combination with Imatinib |
title_full_unstemmed | Depletion of γ-catenin by Histone Deacetylase Inhibition Confers Elimination of CML Stem Cells in Combination with Imatinib |
title_short | Depletion of γ-catenin by Histone Deacetylase Inhibition Confers Elimination of CML Stem Cells in Combination with Imatinib |
title_sort | depletion of γ-catenin by histone deacetylase inhibition confers elimination of cml stem cells in combination with imatinib |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4997248/ https://www.ncbi.nlm.nih.gov/pubmed/27570562 http://dx.doi.org/10.7150/thno.16139 |
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