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Lookup NU author(s): Dr Sarah Fordham, Dr Wei-Yu Lin, Dr Helen Blair, Dr Claire Elstob, Dr Hayden BellORCiD, Dr Rachel PiddockORCiD, Emmanouela Soura, Dr Catherine Park, Dr Thahira Rahman, Abrar Alharbi, Dr Gail Jones, Dr Tobias Menne, Professor Graham Jackson, Dr Helen Marr, Amber Robinson, Emily Bowes, Professor Olaf Heidenreich, Professor James Allan
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2023, Stölzel et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.Precision medicine can significantly improve outcomes for patients with cancer, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here, we describe somatic biallelic TET2 mutations in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine but acutely sensitive to 5′-azacitidine (5′-Aza) hypomethylating monotherapy, resulting in long-term morphological remission. Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5′-Aza. Using an isogenic cell model system and an orthotopic mouse xenograft, we demonstrate that biallelic TET2 mutations confer sensitivity to 5′-Aza compared with cells with monoallelic mutations. Our data argue in favor of using hypomethylating agents for chemoresistant disease or as first-line therapy in patients with biallelic TET2-mutated AML and demonstrate the importance of considering mutant allele dosage in the implementation of precision medicine for patients with cancer.
Author(s): Stolzel F, Fordham SE, Nandana D, Lin W-Y, Blair H, Elstob C, Bell HL, Mohr B, Ruhnke L, Kunadt D, Dill C, Allsop D, Piddock R, Soura E-N, Park C, Fadly M, Rahman T, Alharbi A, Wobus M, Altmann H, Rollig C, Wagenfuhr L, Jones GL, Menne T, Jackson GH, Marr HJ, Fitzgibbon J, Onel K, Meggendorfer M, Robinson A, Bziuk Z, Bowes E, Heidenreich O, Haferlach T, Villar S, Ariceta B, Diaz RA, Altschuler SJ, Wu LF, Prosper F, Montesinos P, Martinez-Lopez J, Bornhauser M, Allan JM
Publication type: Article
Publication status: Published
Journal: JCI Insight
Year: 2023
Volume: 8
Issue: 2
Print publication date: 24/01/2023
Online publication date: 08/12/2022
Acceptance date: 30/11/2022
Date deposited: 09/02/2023
ISSN (electronic): 2379-3708
Publisher: American Society for Clinical Investigation
URL: https://doi.org/10.1172/jci.insight.150368
DOI: 10.1172/jci.insight.150368
PubMed id: 36480300
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