Superoxide-mediated phosphorylation and stabilization of Mcl-1 by AKT underlie venetoclax resistance in hematologic malignancies.

ABSTRACT: Resistance to the Bcl-2-specific inhibitor, Venetoclax (VEN), poses a therapeutic challenge in the management of chronic lymphocytic leukemia and acute myeloid leukemia. Although VEN resistance has been linked to Mcl-1 upregulation, thereby switching survival dependence from Bcl-2 to Mcl-1, the mechanism underlying increased Mcl-1 expression remains elusive. Given that changes in cellular redox state affect cancer cell fate, we investigated the crosstalk between intracellular redox milieu and Mcl-1 upregulation in VEN-resistant cells. Results show that increased Mcl-1 protein levels in VEN-resistant hematologic malignant cells are associated with elevated intracellular superoxide (O₂^.-) levels. Validating that, augmenting intracellular O₂^.- in VE

SUBMITTER: Chong SJF 

PROVIDER: S-EPMC12463670 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature