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Imetelstat-mediated alterations in fatty acid metabolism to induce ferroptosis as a therapeutic strategy for acute myeloid leukemia

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Item Type:Article
Title:Imetelstat-mediated alterations in fatty acid metabolism to induce ferroptosis as a therapeutic strategy for acute myeloid leukemia
Creators Name:Bruedigam, C. and Porter, A.H. and Song, A. and Vroeg In de Wei, G. and Stoll, T. and Straube, J. and Cooper, L. and Cheng, G. and Kahl, V.F.S. and Sobinoff, A.P. and Ling, V.Y. and Jebaraj, B.M.C. and Janardhanan, Y. and Haldar, R. and Bray, L.J. and Bullinger, L. and Heidel, F.H. and Kennedy, G.A. and Hill, M.M. and Pickett, H.A. and Abdel-Wahab, O. and Hartel, G. and Lane, S.W.
Abstract:Telomerase enables replicative immortality in most cancers including acute myeloid leukemia (AML). Imetelstat is a first-in-class telomerase inhibitor with clinical efficacy in myelofibrosis and myelodysplastic syndromes. Here, we develop an AML patient-derived xenograft resource and perform integrated genomics, transcriptomics and lipidomics analyses combined with functional genetics to identify key mediators of imetelstat efficacy. In a randomized phase II-like preclinical trial in patient-derived xenografts, imetelstat effectively diminishes AML burden and preferentially targets subgroups containing mutant NRAS and oxidative stress-associated gene expression signatures. Unbiased, genome-wide CRISPR/Cas9 editing identifies ferroptosis regulators as key mediators of imetelstat efficacy. Imetelstat promotes the formation of polyunsaturated fatty acid-containing phospholipids, causing excessive levels of lipid peroxidation and oxidative stress. Pharmacological inhibition of ferroptosis diminishes imetelstat efficacy. We leverage these mechanistic insights to develop an optimized therapeutic strategy using oxidative stress-inducing chemotherapy to sensitize patient samples to imetelstat causing substantial disease control in AML.
Keywords:Acute Myeloid Leukemia, Fatty Acids, Ferroptosis, Oligonucleotides, Telomerase
Source:Nature Cancer
ISSN:2662-1347
Publisher:Springer Nature
Volume:5
Number:1
Page Range:47-65
Date:January 2024
Official Publication:https://doi.org/10.1038/s43018-023-00653-5
PubMed:View item in PubMed

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