A novel FOXM1-BCL2A1 axis determines unfavourable response to venetoclax in AML.

Abstract

Forkhead box M1 (FOXM1), a Forkhead family transcription factor, is often overexpressed in a variety of human cancers, including AML and strongly associated with therapy resistance and unfavourable outcomes. In AML with NPM1 mutations NPM1/FOXM1 complex sequesters FOXM1 in the cytoplasm and confers favourable treatment outcomes for AML patients, because of FOXM1 inactivation. Inhibition of FOXM1 in AML cell lines and animal models of AML sensitizes AML cells to the Bcl2-inhibitor, venetoclax. In a recent study the upregulation of the BCL2-family protein, BCL2A1 conferred resistance to venetoclax and multiple venetoclax combinations.In this study, we investigated FOXM1/BCL2A1 axis and determined that FOXM1 specifically inhibits venetoclax-induced apoptosis in AML via upregulation of BCL2A1.The knockdown of BCL2A1 in AML in the presence of high levels of FOXM1 led to sensitization of AML cells to venetoclax, suggesting that BCL2A1 is a major target of FOXM1 responsible for resistance to venetoclax. Venetoclax in combination with FOXM1 inhibitor STL001 inhibited BCL2A1 and circumvented venetoclax resistance. Pharmacological inhibition of FOXM1/BCL2A1 axis represents a therapeutic strategy to sensitize AML cells to venetoclax-induced apoptosis.