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

Stephen J F Chong1,2,3,4, Jolin X H Lai5, Kartini Iskandar5

  • 1Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore. SJFChong@nus.edu.sg.

Leukemia
|July 24, 2025
PubMed

Insights

Venetoclax (VEN) resistance in leukemia involves increased Mcl-1 protein due to elevated superoxide levels. Targeting this redox-dependent Mcl-1 stability with AKT inhibitors restores VEN sensitivity.

Area of Science:

  • Hematologic Malignancies
  • Cancer Cell Biology
  • Drug Resistance Mechanisms

Background:

  • Venetoclax (VEN) resistance is a significant clinical challenge in chronic lymphocytic leukemia and acute myeloid leukemia.
  • Mcl-1 upregulation is a known mechanism of VEN resistance, shifting cell survival dependence from Bcl-2 to Mcl-1.
  • The precise mechanisms driving Mcl-1 upregulation in VEN-resistant cells remain unclear.

Purpose of the Study:

  • To investigate the role of intracellular redox state in Mcl-1 upregulation and Venetoclax (VEN) resistance.
  • To elucidate the signaling pathways connecting cellular redox balance to Mcl-1 protein stability.
  • To explore therapeutic strategies targeting the identified VEN resistance mechanism.

Main Methods:

  • Analysis of intracellular superoxide (O2.-) levels in VEN-sensitive and VEN-resistant hematologic malignant cells.
  • Assessment of Mcl-1 protein levels, phosphorylation (T163pMcl-1), ubiquitination, and degradation.
  • Pharmacological inhibition of AKT/PKB signaling and redox modulation.
  • Evaluation of combination therapy efficacy in a murine model of VEN-resistant leukemia.

Main Results:

  • VEN-resistant cells exhibit significantly elevated intracellular superoxide (O2.-) levels.
  • Increased O2.- augments Mcl-1 protein stability by promoting T163 phosphorylation and reducing degradation.
  • Redox-activated AKT/PKB signaling is crucial for O2.--induced Mcl-1 stabilization.
  • Inhibition of AKT or reduction of O2.- restores VEN sensitivity by increasing apoptotic priming.
  • Combination therapy with capivasertib (AKT inhibitor) and VEN reduced tumor burden and prolonged survival in mice.

Conclusions:

  • A novel redox-dependent mechanism contributes to Mcl-1 stability and Venetoclax (VEN) resistance in hematologic malignancies.
  • Intracellular superoxide levels and AKT signaling are key regulators of Mcl-1 stability in this context.
  • Targeting redox pathways and AKT offers a promising therapeutic strategy to overcome VEN resistance.

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