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BRD4 degradation blocks expression of MYC and multiple forms of stem cell resistance in Ph(+) chronic myeloid leukemia
In most patients with chronic myeloid leukemia (CML) clonal cells can be kept under control by BCR::ABL1 tyrosine kinase inhibitors (TKI). However, overt resistance or intolerance against these TKI may occur. We identified the epigenetic reader BRD4 and its downstream‐effector MYC as growth regulato...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley & Sons, Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9546315/ https://www.ncbi.nlm.nih.gov/pubmed/35794848 http://dx.doi.org/10.1002/ajh.26650 |
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author | Peter, Barbara Eisenwort, Gregor Sadovnik, Irina Bauer, Karin Willmann, Michael Rülicke, Thomas Berger, Daniela Stefanzl, Gabriele Greiner, Georg Hoermann, Gregor Keller, Alexandra Wolf, Dominik Čulen, Martin Winter, Georg E. Hoffmann, Thomas Schiefer, Ana‐Iris Sperr, Wolfgang R. Zuber, Johannes Mayer, Jiří Valent, Peter |
author_facet | Peter, Barbara Eisenwort, Gregor Sadovnik, Irina Bauer, Karin Willmann, Michael Rülicke, Thomas Berger, Daniela Stefanzl, Gabriele Greiner, Georg Hoermann, Gregor Keller, Alexandra Wolf, Dominik Čulen, Martin Winter, Georg E. Hoffmann, Thomas Schiefer, Ana‐Iris Sperr, Wolfgang R. Zuber, Johannes Mayer, Jiří Valent, Peter |
author_sort | Peter, Barbara |
collection | PubMed |
description | In most patients with chronic myeloid leukemia (CML) clonal cells can be kept under control by BCR::ABL1 tyrosine kinase inhibitors (TKI). However, overt resistance or intolerance against these TKI may occur. We identified the epigenetic reader BRD4 and its downstream‐effector MYC as growth regulators and therapeutic targets in CML cells. BRD4 and MYC were found to be expressed in primary CML cells, CD34(+)/CD38(−) leukemic stem cells (LSC), and in the CML cell lines KU812, K562, KCL22, and KCL22(T315I). The BRD4‐targeting drug JQ1 was found to suppress proliferation in KU812 cells and primary leukemic cells in the majority of patients with chronic phase CML. In the blast phase of CML, JQ1 was less effective. However, the BRD4 degrader dBET6 was found to block proliferation and/or survival of primary CML cells in all patients tested, including blast phase CML and CML cells exhibiting the T315I variant of BCR::ABL1. Moreover, dBET6 was found to block MYC expression and to synergize with BCR::ABL1 TKI in inhibiting the proliferation in the JQ1‐resistant cell line K562. Furthermore, BRD4 degradation was found to overcome osteoblast‐induced TKI resistance of CML LSC in a co‐culture system and to block interferon‐gamma‐induced upregulation of the checkpoint antigen PD‐L1 in LSC. Finally, dBET6 was found to suppress the in vitro survival of CML LSC and their engraftment in NSG mice. Together, targeting of BRD4 and MYC through BET degradation sensitizes CML cells against BCR::ABL1 TKI and is a potent approach to overcome multiple forms of drug resistance in CML LSC. |
format | Online Article Text |
id | pubmed-9546315 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley & Sons, Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-95463152022-10-14 BRD4 degradation blocks expression of MYC and multiple forms of stem cell resistance in Ph(+) chronic myeloid leukemia Peter, Barbara Eisenwort, Gregor Sadovnik, Irina Bauer, Karin Willmann, Michael Rülicke, Thomas Berger, Daniela Stefanzl, Gabriele Greiner, Georg Hoermann, Gregor Keller, Alexandra Wolf, Dominik Čulen, Martin Winter, Georg E. Hoffmann, Thomas Schiefer, Ana‐Iris Sperr, Wolfgang R. Zuber, Johannes Mayer, Jiří Valent, Peter Am J Hematol Research Articles In most patients with chronic myeloid leukemia (CML) clonal cells can be kept under control by BCR::ABL1 tyrosine kinase inhibitors (TKI). However, overt resistance or intolerance against these TKI may occur. We identified the epigenetic reader BRD4 and its downstream‐effector MYC as growth regulators and therapeutic targets in CML cells. BRD4 and MYC were found to be expressed in primary CML cells, CD34(+)/CD38(−) leukemic stem cells (LSC), and in the CML cell lines KU812, K562, KCL22, and KCL22(T315I). The BRD4‐targeting drug JQ1 was found to suppress proliferation in KU812 cells and primary leukemic cells in the majority of patients with chronic phase CML. In the blast phase of CML, JQ1 was less effective. However, the BRD4 degrader dBET6 was found to block proliferation and/or survival of primary CML cells in all patients tested, including blast phase CML and CML cells exhibiting the T315I variant of BCR::ABL1. Moreover, dBET6 was found to block MYC expression and to synergize with BCR::ABL1 TKI in inhibiting the proliferation in the JQ1‐resistant cell line K562. Furthermore, BRD4 degradation was found to overcome osteoblast‐induced TKI resistance of CML LSC in a co‐culture system and to block interferon‐gamma‐induced upregulation of the checkpoint antigen PD‐L1 in LSC. Finally, dBET6 was found to suppress the in vitro survival of CML LSC and their engraftment in NSG mice. Together, targeting of BRD4 and MYC through BET degradation sensitizes CML cells against BCR::ABL1 TKI and is a potent approach to overcome multiple forms of drug resistance in CML LSC. John Wiley & Sons, Inc. 2022-07-18 2022-09 /pmc/articles/PMC9546315/ /pubmed/35794848 http://dx.doi.org/10.1002/ajh.26650 Text en © 2022 The Authors. American Journal of Hematology published by Wiley Periodicals LLC. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Peter, Barbara Eisenwort, Gregor Sadovnik, Irina Bauer, Karin Willmann, Michael Rülicke, Thomas Berger, Daniela Stefanzl, Gabriele Greiner, Georg Hoermann, Gregor Keller, Alexandra Wolf, Dominik Čulen, Martin Winter, Georg E. Hoffmann, Thomas Schiefer, Ana‐Iris Sperr, Wolfgang R. Zuber, Johannes Mayer, Jiří Valent, Peter BRD4 degradation blocks expression of MYC and multiple forms of stem cell resistance in Ph(+) chronic myeloid leukemia |
title |
BRD4 degradation blocks expression of MYC and multiple forms of stem cell resistance in Ph(+) chronic myeloid leukemia |
title_full |
BRD4 degradation blocks expression of MYC and multiple forms of stem cell resistance in Ph(+) chronic myeloid leukemia |
title_fullStr |
BRD4 degradation blocks expression of MYC and multiple forms of stem cell resistance in Ph(+) chronic myeloid leukemia |
title_full_unstemmed |
BRD4 degradation blocks expression of MYC and multiple forms of stem cell resistance in Ph(+) chronic myeloid leukemia |
title_short |
BRD4 degradation blocks expression of MYC and multiple forms of stem cell resistance in Ph(+) chronic myeloid leukemia |
title_sort | brd4 degradation blocks expression of myc and multiple forms of stem cell resistance in ph(+) chronic myeloid leukemia |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9546315/ https://www.ncbi.nlm.nih.gov/pubmed/35794848 http://dx.doi.org/10.1002/ajh.26650 |
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