Intracellular Cholesterol Pools Regulate Oncogenic Signaling and Epigenetic Circuitries in Early T-cell Precursor Acute Lymphoblastic Leukemia
Rashkovan, Marissa (Columbia University Irving Medical Center)
Albero, Robert (Columbia University Irving Medical Center)
Gianni, Francesca (Columbia University Irving Medical Center)
Perez-Duran, Pablo (Columbia University Irving Medical Center)
Miller, Hannah I. (Columbia University Irving Medical Center)
Mackey, Adam L. (Columbia University Irving Medical Center)
Paietta, Elisabeth M. (Montefiore Medical Center)
Tallman, Martin S. (Memorial Sloan Kettering Cancer Center)
Rowe, Jacob M. (Shaare Zedek Medical Center (Jerusalem, Israel))
Litzow, Mark R. (Mayo Clinic)
Wiernik, Peter H. (Cancer Research Foundation of New York)
Luger, Selina (Cancer Research Foundation of New York)
Sulis, Maria Luisa (Memorial Sloan Kettering Cancer Center)
Soni, Rajesh Kumar (Columbia University Irving Medical Center)
Ferrando, Adolfo A. (Columbia University)

Fecha:	2022
Resumen:	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.
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Lengua:	Anglès
Documento:	Article ; recerca ; Versió acceptada per publicar
Materia:	Early T-cell acute lymphoblastic leukemia ; ETP-ALL ; T-cell acute lymphoblastic leukemia ; TALL ; Mevalonate synthesis pathway ; Cholesterol ; Statins ; 3-hydroxy-3-methylglutaryl-CoA Reductase (HMGCR) ; MYC ; AKT1
Publicado en:	Cancer Discovery, Vol. 12 Núm. 3 (January 2022) , p. 856-871, ISSN 2159-8290

DOI: 10.1158/2159-8290.CD-21-0551
PMID: 34711640

Postprint 46 p, 8.4 MB

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