A novel FOXM1–BCL2A1 axis determines unfavorable response to venetoclax in AML

Forkhead box M1 (FOXM1), a Forkhead family transcription factor, is often overexpressed in a variety of human cancers, including acute myeloid leukemia (AML), and is strongly associated with therapy resistance and unfavorable outcomes. In AML with NPM1 mutations, NPM1-FOXM1 complex sequesters FOXM1 in the cytoplasm and confers favorable 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 the 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 the FOXM1-BCL2A1 axis represents a therapeutic strategy to sensitize AML cells to venetoclax-induced apoptosis.