Intracellular cholesterol pools regulate oncogenic signaling and epigenetic circuitries in early T-cell precursor acute lymphoblastic leukemia Journal Article
| Authors: | Rashkovan, M.; Albero, R.; Gianni, F.; Perez-Duran, P.; Miller, H. I.; Mackey, A. L.; Paietta, E. M.; Tallman, M. S.; Rowe, J. M.; Litzow, M. R.; Wiernik, P. H.; Luger, S.; Sulis, M. L.; Soni, R. K.; Ferrando, A. A. |
| Article Title: | Intracellular cholesterol pools regulate oncogenic signaling and epigenetic circuitries in early T-cell precursor acute lymphoblastic leukemia |
| 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. This article is highlighted in the In This Issue feature, p. 587. ©2021 American Association for Cancer Research. |
| Journal Title: | Cancer Discovery |
| Volume: | 12 |
| Issue: | 3 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2022-03-01 |
| Start Page: | 856 |
| End Page: | 871 |
| Language: | English |
| DOI: | 10.1158/2159-8290.Cd-21-0551 |
| PUBMED: | 34711640 |
| PROVIDER: | scopus |
| PMCID: | PMC8904296 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 April 2022 -- Source: Scopus |
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