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

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

doi:10.3389/fonc.2021.696532

Mikhail S Chesnokov, Soheila Borhani + Show 4 more

Open Access

https://doi.org/10.3389/fonc.2021.696532

Copy DOI

Abstract

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.

Highlights

Forkhead box protein M1 (FOXM1) has emerged as a key contributor to cell proliferation and renewal as well as tumorigenesis
We report for the first time that FOXM1 inactivation in Acute myeloid leukemia (AML) cells can sensitize them to Bcl-2 inhibitor venetoclax that is considered as a very promising agent for AML treatment
We investigated the role of FOXM1-AKT interconnection in AML using FLT3-wild-type KG-1 and THP-1 human AML cell lines, as FLT3-ITD mutation can promote AKT activity regardless of FOXM1 status

Summary

Introduction

Forkhead box protein M1 (FOXM1) has emerged as a key contributor to cell proliferation and renewal as well as tumorigenesis. FOXM1 overexpression occurs in many human cancers, including hematopoietic malignancies, and plays a crucial role in cancer development and progression, serving both as a potent effector of tumor development and prognostic indicator for patients [1,2,3]. High FOXM1 levels are generally associated with chemoresistance of malignant cells, aggressive tumor phenotype, and poor prognosis due to decreased efficacy of common therapeutic strategies [2, 3]. FOXM1-AKT Regulation Loop in AML cells is directly associated with treatment resistance and inferior survival in AML patients [4, 5]. Our discovery of interaction between FOXM1 and nucleophosmin (NPM, encoded by NPM1 gene) suggested that high chemosensitivity of AML cells expressing mutant NPM (NPMmut) may be closely associated with FOXM1 inactivation due to its relocalization to cytoplasm [4,5,6]. FOXM1 is a promising target in AML, and its inactivation may potentially be used to overcome drug resistance [7]

Methods

Results

Conclusion