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.

• Authors: Marissa Rashkovan, Robert Albero, Francesca Gianni, Pablo Perez-Duran, Hannah I Miller, Adam L Mackey, Elisabeth M Paietta, Martin S Tallman, Jacob M Rowe, Mark R Litzow, Peter H Wiernik, Selina Luger, Maria Luisa Sulis, Rajesh K Soni, Adolfo A Ferrando
• Journal: Cancer discovery (Cancer Discov) Vol. 12 Issue 3 Pg. 856-871 (03 01 2022) ISSN: 2159-8290 [Electronic] United States
• PMID: 34711640 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Proto-Oncogene Proteins c-myc
• Cholesterol
• Mevalonic Acid

Topics

• Carcinogenesis (metabolism)
• Cholesterol (metabolism)
• Epigenesis, Genetic
• Humans
• Mevalonic Acid (metabolism)
• Precursor Cells, T-Lymphoid (metabolism, pathology)
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (pathology)
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• Signal Transduction