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 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

SUBMITTER: Peter B 

PROVIDER: S-EPMC9546315 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature