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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Friedrich Stölzel - (Author)
  • Sarah E Fordham - , Newcastle upon Tyne Hospitals NHS Foundation Trust (Author)
  • Devi Nandana - , Newcastle upon Tyne Hospitals NHS Foundation Trust (Author)
  • Wei-Yu Lin - , Newcastle upon Tyne Hospitals NHS Foundation Trust (Author)
  • Helen Blair - , Newcastle upon Tyne Hospitals NHS Foundation Trust (Author)
  • Claire Elstob - , Newcastle upon Tyne Hospitals NHS Foundation Trust (Author)
  • Hayden L Bell - , Newcastle upon Tyne Hospitals NHS Foundation Trust (Author)
  • Brigitte Mohr - , Department of internal Medicine I (Author)
  • Leo Ruhnke - , Department of internal Medicine I (Author)
  • Desiree Kunadt - , Department of internal Medicine I, University Hospital Carl Gustav Carus Dresden (Author)
  • Claudia Dill - , Department of internal Medicine I (Author)
  • Daniel Allsop - , Newcastle upon Tyne Hospitals NHS Foundation Trust (Author)
  • Rachel Piddock - , Newcastle upon Tyne Hospitals NHS Foundation Trust (Author)
  • Emmanouela-Niki Soura - , Newcastle upon Tyne Hospitals NHS Foundation Trust (Author)
  • Catherine Park - , Newcastle upon Tyne Hospitals NHS Foundation Trust (Author)
  • Mohd Fadly - , Newcastle upon Tyne Hospitals NHS Foundation Trust (Author)
  • Thahira Rahman - , Newcastle upon Tyne Hospitals NHS Foundation Trust (Author)
  • Abrar Alharbi - , Newcastle upon Tyne Hospitals NHS Foundation Trust (Author)
  • Manja Wobus - , Department of internal Medicine I (Author)
  • Heidi Altmann - , Department of internal Medicine I (Author)
  • Christoph Röllig - , Department of internal Medicine I, University Hospital Carl Gustav Carus Dresden (Author)
  • Lisa Wagenführ - , Department of internal Medicine I, University Hospital Carl Gustav Carus Dresden (Author)
  • Gail L Jones - , Newcastle upon Tyne Hospitals NHS Foundation Trust (Author)
  • Tobias Menne - , Newcastle upon Tyne Hospitals NHS Foundation Trust (Author)
  • Graham H Jackson - , Newcastle upon Tyne Hospitals NHS Foundation Trust (Author)
  • Helen J Marr - , Newcastle upon Tyne Hospitals NHS Foundation Trust (Author)
  • Jude Fitzgibbon - , Queen Mary University of London (Author)
  • Kenan Onel - , Icahn School of Medicine at Mount Sinai (Author)
  • Manja Meggendorfer - , Munich Leukemia Laboratory (Author)
  • Amber Robinson - , Newcastle upon Tyne Hospitals NHS Foundation Trust (Author)
  • Zuzanna Bziuk - , Newcastle upon Tyne Hospitals NHS Foundation Trust (Author)
  • Emily Bowes - , Newcastle upon Tyne Hospitals NHS Foundation Trust (Author)
  • Olaf Heidenreich - , Newcastle upon Tyne Hospitals NHS Foundation Trust (Author)
  • Torsten Haferlach - , Munich Leukemia Laboratory (Author)
  • Sara Villar - , University Hospital Navarra (CUN) (Author)
  • Beñat Ariceta - , University of Navarra (Author)
  • Rosa Ayala Diaz - , Complutense University (Author)
  • Steven J Altschuler - , University of California at Davis (Author)
  • Lani F Wu - , University of California at Davis (Author)
  • Felipe Prosper - , University Hospital Navarra (CUN) (Author)
  • Pau Montesinos - , Hospital Universitario La Fe (Author)
  • Joaquin Martinez-Lopez - , Complutense University (Author)
  • Martin Bornhäuser - , National Center for Tumor Diseases (Partners: UKD, MFD, HZDR, DKFZ), Department of internal Medicine I, University Hospital Carl Gustav Carus Dresden (Author)
  • James M Allan - , Newcastle upon Tyne Hospitals NHS Foundation Trust (Author)

Abstract

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.

Details

Original languageEnglish
Article numbere150368
JournalJCI insight
Volume8
Issue number2
Publication statusPublished - 24 Jan 2023
Peer-reviewedYes

External IDs

PubMedCentral PMC9977313
Scopus 85147047026

Keywords

Sustainable Development Goals

Keywords

  • Humans, Mice, Animals, Azacitidine, Leukemia, Myeloid, Acute/genetics, Kaplan-Meier Estimate, Mutation, DNA-Binding Proteins/genetics, Dioxygenases/genetics