Institute for Cancer Genetics, Columbia University Irving Medical Center, New York, New York.
Montefiore Medical Center, Bronx, New York.
Cancer Discov. 2022 Mar 1;12(3):856-871. doi: 10.1158/2159-8290.CD-21-0551.
Early T-cell acute lymphoblastic leukemia (ETP-ALL) is an aggressive hematologic malignancy associated with early relapse and poor prognosis that is genetically, immunophenotypically, and transcriptionally distinct from more mature T-cell acute lymphoblastic leukemia (T-ALL) tumors. Here, we leveraged global metabolomic and transcriptomic profiling of primary ETP- and T-ALL leukemia samples to identify specific metabolic circuitries differentially active in this high-risk leukemia group. ETP-ALLs showed increased biosynthesis of phospholipids and sphingolipids and were specifically sensitive to inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting enzyme in the mevalonate pathway. Mechanistically, inhibition of cholesterol synthesis inhibited oncogenic AKT1 signaling and suppressed MYC expression via loss of chromatin accessibility at a leukemia stem cell-specific long-range MYC enhancer. In all, these results identify the mevalonate pathway as a druggable novel vulnerability in high-risk ETP-ALL cells and uncover an unanticipated critical role for cholesterol biosynthesis in signal transduction and epigenetic circuitries driving leukemia cell growth and survival.
Overtly distinct cell metabolic pathways operate in ETP- and T-ALL pointing to specific metabolic vulnerabilities. Inhibition of mevalonate biosynthesis selectively blocks oncogenic AKT-MYC signaling in ETP-ALL and suppresses leukemia cell growth. Ultimately, these results will inform the development of novel tailored and more effective treatments for patients with high-risk ETP-ALL. This article is highlighted in the In This Issue feature, p. 587.
早期 T 细胞急性淋巴细胞白血病（ETP-ALL）是一种侵袭性血液恶性肿瘤，与早期复发和预后不良相关，其在遗传、免疫表型和转录水平上与更成熟的 T 细胞急性淋巴细胞白血病（T-ALL）肿瘤不同。在这里，我们利用原发性 ETP-ALL 和 T-ALL 白血病样本的全局代谢组学和转录组学分析，确定了在这一高危白血病组中差异活跃的特定代谢途径。ETP-ALL 显示出磷脂和鞘脂生物合成增加，并且对 3-羟基-3-甲基戊二酰辅酶 A 还原酶（甲羟戊酸途径的限速酶）的抑制特别敏感。从机制上讲，胆固醇合成的抑制通过在白血病干细胞特异性长距离 MYC 增强子处丧失染色质可及性，抑制致癌 AKT1 信号和抑制 MYC 表达。总之，这些结果表明甲羟戊酸途径是高危 ETP-ALL 细胞中可靶向的新脆弱性，并揭示了胆固醇生物合成在信号转导和表观遗传通路中驱动白血病细胞生长和存活的意想不到的关键作用。
ETP-ALL 和 T-ALL 中明显不同的细胞代谢途径表明存在特定的代谢脆弱性。甲羟戊酸生物合成的抑制选择性地阻断 ETP-ALL 中的致癌 AKT-MYC 信号，并抑制白血病细胞的生长。最终，这些结果将为高危 ETP-ALL 患者制定新的、更有效的治疗方法提供信息。本文在本期的特色文章中进行了重点介绍，第 587 页。
