粒单核细胞和单核细胞急性髓系白血病 (AML) 亚型本质上对基于维奈托克的治疗方案具有耐药性。识别可针对的漏洞将限制抵抗和复发。我们之前记录了维奈托克和强心苷 (CG) 组合在 AML 中的协同作用。尽管有临床前证据，但由于缺乏预测性生物标志物，强心苷（CG）在癌症治疗中的重新利用仍然不成功。我们报告说，AML 患者原始细胞的离体反应和已建立的细胞系对半合成 CG UNBS1450 的体外敏感性与 ATPase Na /K 转运亚基 α 1 (ATP1A1)/BCL2 like 1 (BCL2L1) 表达比相关。公开的 AML 数据集将骨髓单核细胞/单核细胞分化确定为最稳健的预后特征，此外还有核心结合因子亚基 β (CBFB)、赖氨酸甲基转移酶 2A (KMT2A) 重排和错义 Fms 相关受体酪氨酸激酶 3 (FLT3) 突变。从机制上讲，BCL2L1 可防止 CG 介导的离子扰动逐步触发、蛋白质合成抑制和 MCL1 下调诱导的细胞死亡。在体内，CG表现出总体可耐受的特征，同时影响肿瘤生长，其效果范围从肿瘤生长抑制到消退。这些发现提出了 CG 在特定 AML 亚型中重新利用的预测标记。© 2023。作者。

Myelomonocytic and monocytic acute myeloid leukemia (AML) subtypes are intrinsically resistant to venetoclax-based regimens. Identifying targetable vulnerabilities would limit resistance and relapse. We previously documented the synergism of venetoclax and cardiac glycoside (CG) combination in AML. Despite preclinical evidence, the repurposing of cardiac glycosides (CGs) in cancer therapy remained unsuccessful due to a lack of predictive biomarkers. We report that the ex vivo response of AML patient blasts and the in vitro sensitivity of established cell lines to the hemi-synthetic CG UNBS1450 correlates with the ATPase Na+/K+ transporting subunit alpha 1 (ATP1A1)/BCL2 like 1 (BCL2L1) expression ratio. Publicly available AML datasets identify myelomonocytic/monocytic differentiation as the most robust prognostic feature, along with core-binding factor subunit beta (CBFB), lysine methyltransferase 2A (KMT2A) rearrangements, and missense Fms-related receptor tyrosine kinase 3 (FLT3) mutations. Mechanistically, BCL2L1 protects from cell death commitment induced by the CG-mediated stepwise triggering of ionic perturbation, protein synthesis inhibition, and MCL1 downregulation. In vivo, CGs showed an overall tolerable profile while impacting tumor growth with an effect ranging from tumor growth inhibition to regression. These findings suggest a predictive marker for CG repurposing in specific AML subtypes.© 2023. The Author(s).