FOXM1-AKT Positive Regulation Loop Provides Venetoclax Resistance in AML

Mikhail S. Chesnokov, Soheila Borhani, Marianna Halasi, Zarema Arbieva, Irum Khan*, Andrei L. Gartel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Forkhead box protein M1 (FOXM1) is a crucial regulator of cancer development and chemoresistance. It is often overexpressed in acute myeloid leukemia (AML) and is associated with poor survival and reduced efficacy of cytarabine therapy. Molecular mechanisms underlying high FOXM1 expression levels in malignant cells are still unclear. Here we demonstrate that AKT and FOXM1 constitute a positive autoregulatory loop in AML cells that sustains high activity of both pro-oncogenic regulators. Inactivation of either AKT or FOXM1 signaling results in disruption of whole loop, coordinated suppression of FOXM1 or AKT, respectively, and similar transcriptomic changes. AML cells with inhibited AKT activity or stable FOXM1 knockdown display increase in HOXA genes expression and BCL2L1 suppression that are associated with prominent sensitization to treatment with Bcl-2 inhibitor venetoclax. Taken together, our data indicate that AKT and FOXM1 in AML cells should not be evaluated as single independent regulators but as two parts of a common FOXM1-AKT positive feedback circuit. We also report for the first time that FOXM1 inactivation can overcome AML venetoclax resistance. Thus, targeting FOXM1-AKT loop may open new possibilities in overcoming AML drug resistance and improving outcomes for AML patients.

Original languageEnglish (US)
Article number696532
JournalFrontiers in Oncology
StatePublished - Jul 26 2021


  • AKT pathway
  • FOXM1
  • HOXA gene family
  • acute myeloid leukemia
  • drug resistance
  • positive feedback loop
  • venetoclax

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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