@article{7be311051376441493f9b83980212072,
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.",
author = "Marissa Rashkovan and Robert Albero and Francesca Gianni and Pablo Perez-Duran and Miller, {Hannah I.} and Mackey, {Adam L.} and Paietta, {Elisabeth M.} and Tallman, {Martin S.} and Rowe, {Jacob M.} and Litzow, {Mark R.} and Wiernik, {Peter H.} and Selina Luger and Sulis, {Maria Luisa} and Soni, {Rajesh K.} and Ferrando, {Adolfo A.}",
note = "Funding Information: M. Rashkovan reports grants from the Damon Runyon Cancer Research Foundation during the conduct of the study. M.S. Tallman reports grants from AbbVie, Orsenix, Biosight, Glycomimetics, Rafael Pharmaceuticals, and Amgen and other support from AbbVie, Daiichi Sankyo, Orsenix, KAHR, Rigel, Delta Fly Pharma, Tetraphase, Onco-lyze, Jazz Pharma, Roche, Biosight, Novartis, Innate Pharmaceuticals, Kura, Syros Pharmaceuticals, and Ipsen Biopharmaceuticals outside the submitted work, and is Past President of the American Society of Hematology (2021). A.A. Ferrando reports grants from the NCI and Alex{\textquoteright}s Lemonade Stand Foundation during the conduct of the study; personal fees from Bristol Myers Squib, the American Society of Hematology, SpringWorks Therapeutics, and VantAI and grants from Hyundai, the Leukemia & Lymphoma Society, Pershing Square Sohn Cancer Research Alliance, and Alex{\textquoteright}s Lemonade Stand Foundation outside the submitted work; and a patent for 20130064810 issued, a patent for 20110118192 issued, a patent for 20100093684 issued, a patent for 20100087358 issued, and a patent for 20150299801 issued. No disclosures were reported by the other authors. Funding Information: This work was supported by the St. Baldrick{\textquoteright}s Foundation (A.A. Ferrando); the Chemotherapy Foundation (A.A. Ferrando); a Crazy 8 Pilot Project Award from Alex{\textquoteright}s Lemonade Stand Foundation (A.A. Ferrando); and the NIH grants P30 CA013696 (Genomics and High-Throughput Screen Shared Resource, Flow Cytometry Shared Resource, Oncology Precision Therapeutics Shared Resource), R35 CA210065 (A.A. Ferrando), UG1 CA233332 (A.A. Ferrando, ECOG-ACRIN), CA180827 (E.M. Paietta), CA196172 (E.M. Paietta), UG1 CA232760 (M.R. Litzow), UG1 CA233290 (M.S. Tallman), CA180820 (ECOG-ACRIN), CA189859 (ECOG-ACRIN), and CA233332 (ECOG-ACRIN). M. Rashkovan is a Damon Runyon-Sohn Pediatric Cancer Fellow supported by the Damon Runyon Cancer Research Foundation (DRSG-2017). R. Albero is supported by a Leukemia & Lymphoma Society postdoctoral fellowship. F. Gianni is supported by an American–Italian Cancer Foundation postdoctoral fellowship. Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research.",
year = "2022",
month = mar,
day = "1",
doi = "10.1158/2159-8290.CD-21-0551",
language = "English (US)",
volume = "12",
pages = "856--871",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "3",
}