Abstract
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. SIGNIFICANCE: 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.
Original language | English (US) |
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Pages (from-to) | 856-871 |
Number of pages | 16 |
Journal | Cancer discovery |
Volume | 12 |
Issue number | 3 |
DOIs | |
State | Published - Mar 1 2022 |
Externally published | Yes |
ASJC Scopus subject areas
- Oncology