J 2022

BRD4 degradation blocks expression of MYC and multiple forms of stem cell resistance in Ph+ chronic myeloid leukemia

PETER, Barbara, Gregor EISENWORT, Irina SADOVNIK, Karin BAUER, Michael WILLMANN et. al.

Basic information

Original name

BRD4 degradation blocks expression of MYC and multiple forms of stem cell resistance in Ph+ chronic myeloid leukemia

Authors

PETER, Barbara, Gregor EISENWORT, Irina SADOVNIK, Karin BAUER, Michael WILLMANN, Thomas RUELICKE, Daniela BERGER, Gabriele STEFANZL, Georg GREINER, Gregor HOERMANN, Alexandra KELLER, Dominik WOLF, Martin ČULEN (703 Slovakia, belonging to the institution), Georg E WINTER, Thomas HOFFMANN, Ana-Iris SCHIEFER, Wolfgang R SPERR, Johannes ZUBER, Jiří MAYER (203 Czech Republic, belonging to the institution) and Peter VALENT (guarantor)

Edition

American Journal of Hematology, Hoboken, John Wiley & Sons, 2022, 0361-8609

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30205 Hematology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

Impact factor

Impact factor: 12.800

RIV identification code

RIV/00216224:14110/22:00127384

Organization unit

Faculty of Medicine

DOI

UT WoS

000826289800001

Keywords in English

chronic myeloid leukemia; stem cell resistance; BRD4 degradation blocks expression; MYC

Tags

Tags

International impact, Reviewed
Změněno: 8/12/2022 12:35, Mgr. Tereza Miškechová

Abstract

V originále

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.