BRD4 degradation blocks expression of MYC and multiple forms of stem cell resistance in Ph+ chronic myeloid leukemia
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F65269705%3A_____%2F22%3A00076430" target="_blank" >RIV/65269705:_____/22:00076430 - isvavai.cz</a>
Alternative codes found
RIV/00216224:14110/22:00127384
Result on the web
<a href="https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.26650" target="_blank" >https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.26650</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1002/ajh.26650" target="_blank" >10.1002/ajh.26650</a>
Alternative languages
Result language
angličtina
Original language name
BRD4 degradation blocks expression of MYC and multiple forms of stem cell resistance in Ph+ chronic myeloid leukemia
Original language 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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30205 - Hematology
Result continuities
Project
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Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2022
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
American journal of hematology
ISSN
0361-8609
e-ISSN
1096-8652
Volume of the periodical
97
Issue of the periodical within the volume
9
Country of publishing house
US - UNITED STATES
Number of pages
11
Pages from-to
1215-1225
UT code for WoS article
000826289800001
EID of the result in the Scopus database
2-s2.0-85134396880