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

Abstract

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 KCL22T315I. 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.

BCR-ABL triggers a glucose-dependent survival program during leukemogenesis through the suppression of TXNIP

“…We demonstrate the effective cell growth suppression during combination of JQ1 with imatinib for treatment of either the primitive CML samples and the mouse CML-like disease model. In line with the previous report that JQ1 cooperates with BCR/ABL TKI in inducing Ph + CML growth-inhibition [ 46 ], we further point out that the synergistic inhibitory effect is predominantly due to the suppression of TXNIP. Supporting this idea, TXNIP suppression with SBI477 counteracted imatinib-mediated suppression of cell survival in the primitive CML samples.…”

CJ2: A Novel Potent Platinum(IV) Prodrug Enhances Chemo-Immunotherapy by Facilitating PD-L1 Degradation in the Cytoplasm and Cytomembrane

“…Proto-oncogene C-MYC is often related to cancer proliferation and deterioration . Its transcription highly depends on BRD4 and is activated aberrantly in human malignancies . Moreover, C-MYC can induce expression of various proteins including PD-L1 to form an immunosuppressive microenvironment.…”

The Bone Marrow Immune Microenvironment in CML: Treatment Responses, Treatment-Free Remission, and Therapeutic Vulnerabilities

“…Other means of inhibition may counteract PD-L1 activity. BRD4 degradation was found to reduce PD-L1 upregulation on CML LSCs, which is attributed to both inhibition of IFN-γ-mediated upregulation and because the PDL1 gene is a target of BRD4 [82]. Pharmacological inhibition of inflammatory mediators IRAK1 and IRAK4 may also reduce PD-L1 expression on CML LSCs [83].…”