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Intracellular cholesterol pools regulate oncogenic signaling and epigenetic circuitries in Early T-cell Precursor Acute Lymphoblastic Leukemia.

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 (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 (HMGCR), 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.