端粒酶能够在大多数癌症中实现复制永生，包括急性髓系白血病 (AML)。 Imetelstat 是一种一流的端粒酶抑制剂，对骨髓纤维化和骨髓增生异常综合征具有临床疗效。在这里，我们开发了 AML 患者来源的异种移植资源，并结合功能遗传学进行综合基因组学、转录组学和脂质组学分析，以确定 imetelstat 疗效的关键介质。在一项针对患者来源的异种移植物的随机 II 期临床前试验中，imetelstat 有效减轻了 AML 负担，并优先针对包含突变 NRAS 和氧化应激相关基因表达特征的亚组。无偏见的全基因组 CRISPR/Cas9 编辑将铁死亡调节因子确定为 imetelstat 功效的关键调节因子。伊美司他促进含多不饱和脂肪酸磷脂的形成，导致脂质过氧化和氧化应激水平过高。铁死亡的药理学抑制会降低伊美司他的疗效。我们利用这些机制见解来开发优化的治疗策略，使用氧化应激诱导化疗使患者样本对 imetelstat 敏感，从而使 AML 的疾病得到实质性控制。© 2023。作者。

Telomerase enables replicative immortality in most cancers including acute myeloid leukemia (AML). Imetelstat is a first-in-class telomerase inhibitor with clinical efficacy in myelofibrosis and myelodysplastic syndromes. Here, we develop an AML patient-derived xenograft resource and perform integrated genomics, transcriptomics and lipidomics analyses combined with functional genetics to identify key mediators of imetelstat efficacy. In a randomized phase II-like preclinical trial in patient-derived xenografts, imetelstat effectively diminishes AML burden and preferentially targets subgroups containing mutant NRAS and oxidative stress-associated gene expression signatures. Unbiased, genome-wide CRISPR/Cas9 editing identifies ferroptosis regulators as key mediators of imetelstat efficacy. Imetelstat promotes the formation of polyunsaturated fatty acid-containing phospholipids, causing excessive levels of lipid peroxidation and oxidative stress. Pharmacological inhibition of ferroptosis diminishes imetelstat efficacy. We leverage these mechanistic insights to develop an optimized therapeutic strategy using oxidative stress-inducing chemotherapy to sensitize patient samples to imetelstat causing substantial disease control in AML.© 2023. The Author(s).