Raghuwanshi Sanjeev, Magdy Ahmed, Hay Nissim, Gartel Andrei
University of Illinois at Chicago, Department of Medicine, Chicago, Illinois, USA.
University of Illinois at Chicago, Department of Biochemistry and Molecular Genetics, Chicago, Illinois, USA.
J Biol Chem. 2025 Mar;301(3):108240. doi: 10.1016/j.jbc.2025.108240. Epub 2025 Jan 27.
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.
叉头框蛋白M1（FOXM1）是一种叉头家族转录因子，在包括急性髓系白血病（AML）在内的多种人类癌症中常过度表达，且与治疗耐药性及不良预后密切相关。在伴有核磷蛋白1（NPM1）突变的AML中，NPM1 - FOXM1复合物将FOXM1隔离于细胞质中，由于FOXM1失活，从而使AML患者获得良好的治疗效果。在AML细胞系及AML动物模型中抑制FOXM1可使AML细胞对BCL2抑制剂维奈克拉敏感。在最近一项研究中，BCL2家族蛋白BCL2A1的上调赋予了对维奈克拉及多种维奈克拉联合用药的耐药性。在本研究中，我们对FOXM1 - BCL2A1轴进行了研究，并确定FOXM1通过上调BCL2A1特异性抑制维奈克拉诱导的AML细胞凋亡。在FOXM1水平较高的情况下，敲低AML中的BCL2A1可使AML细胞对维奈克拉敏感，这表明BCL2A1是FOXM1导致维奈克拉耐药的主要靶点。维奈克拉与FOXM1抑制剂STL001联合使用可抑制BCL2A1并克服维奈克拉耐药性。对FOXM1 - BCL2A1轴的药理学抑制代表了一种使AML细胞对维奈克拉诱导的凋亡敏感的治疗策略。
