Toggle Main Menu Toggle Search

Open Access padlockePrints

Biallelic TET2 mutations confer sensitivity to 5′-azacitidine in acute myeloid leukemia

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

Downloads


Licence

This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 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.


Publication metadata

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


Altmetrics

Altmetrics provided by Altmetric


Funding

Funder referenceFunder name
13044Bloodwise (Formerly Leukaemia and Lymphoma Research)
13044Medical Research Council (MRC)
30015.088.085/PA/IXSJGW Patterson Foundation
C355/A26819
Fondazione AIRC per la Ricerca sul Cancro
German Consortium for Translational Cancer Research Dresden
Fundación Científica de la Asociación Española Contra el Cáncer

Share