FOXM1-AKT Positive Regulation Loop Provides Venetoclax Resistance in AML.

Area of Science:

• Oncology
• Molecular Biology
• Hematology

Background:

• Forkhead box protein M1 (FOXM1) is overexpressed in acute myeloid leukemia (AML), correlating with poor prognosis and cytarabine resistance.
• The precise mechanisms driving elevated FOXM1 levels in AML remain incompletely understood.

Purpose of the Study:

• To elucidate the molecular interplay between AKT and FOXM1 in AML.
• To investigate the therapeutic implications of targeting the FOXM1-AKT axis in AML.

Main Methods:

• Analysis of the FOXM1-AKT signaling pathway in AML cell lines.
• Assessment of gene expression changes following AKT or FOXM1 inhibition.
• Evaluation of drug sensitivity in AML cells with modulated FOXM1-AKT signaling.

Main Results:

• A positive autoregulatory loop between AKT and FOXM1 was identified in AML cells, sustaining their activity.
• Inhibition of either AKT or FOXM1 led to coordinated suppression of the other and similar transcriptomic alterations.
• Targeting the FOXM1-AKT loop increased HOXA gene expression, suppressed BCL2L1, and sensitized cells to venetoclax.

Conclusions:

• FOXM1 and AKT function as a cooperative feedback circuit in AML, not independent regulators.
• Inactivating the FOXM1-AKT loop can overcome venetoclax resistance in AML.
• Targeting this loop presents a novel strategy to improve treatment outcomes for AML patients.