Identification of specific and therapeutically actionable vulnerabilities, ideally present across multiple mutational backgrounds, is needed to improve acute myeloid leukemia (AML) patients’ outcomes. We identify stearoyl-CoA desaturase (SCD), the key enzyme in fatty acid (FA) desaturation, as prognostic of patients' outcomes and, using the clinical-grade inhibitor SSI-4, show that SCD inhibition (SCDi) is a therapeutic vulnerability across multiple AML models in vitro and in vivo. Multiomic analysis demonstrates that SCDi causes lipotoxicity, which induces AML cell death via pleiotropic effects. Sensitivity to SCDi correlates with AML dependency on FA desaturation regardless of mutational profile and is modulated by FA biosynthesis activity. Finally, we show that lipotoxicity increases chemotherapy-induced DNA damage and standard chemotherapy further sensitizes AML cells to SCDi. Our work supports developing FA desaturase inhibitors in AML while stressing the importance of identifying predictive biomarkers of response and biologically validated combination therapies to realize their full therapeutic potential.

需要识别特异性和治疗上可行的脆弱性，理想情况下存在于多个突变背景中，以改善急性髓性白血病 （AML） 患者的预后。我们将脂肪酸 （FA） 去饱和的关键酶硬脂酰辅酶 A 去饱和酶 （SCD） 确定为患者预后的预后，并使用临床级抑制剂 SSI-4 表明 SCD 抑制 （SCDi） 是体外和体内多种 AML 模型的治疗脆弱性。多组学分析表明，SCDi 引起脂毒性，从而通过多效性效应诱导 AML 细胞死亡。对 SCDi 的敏感性与 AML 对 FA 去饱和度的依赖性相关，无论突变特征如何，并受 FA 生物合成活性的调节。最后，我们表明脂毒性会增加化疗诱导的 DNA 损伤，而标准化疗进一步使 AML 细胞对 SCDi 敏感。我们的工作支持在 AML 中开发 FA 去饱和酶抑制剂，同时强调识别反应的预测生物标志物和经过生物学验证的联合疗法以实现其全部治疗潜力的重要性。