Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Biallelic TET2 mutations confer sensitivity to 5′-azacitidine in acute myeloid leukemia
Friedrich Stölzel, … , Martin Bornhäuser, James M. Allan
Friedrich Stölzel, … , Martin Bornhäuser, James M. Allan
Published December 8, 2022
Citation Information: JCI Insight. 2023;8(2):e150368. https://doi.org/10.1172/jci.insight.150368.
View: Text | PDF
Research Article Hematology

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

  • Text
  • PDF
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.

Authors

Friedrich Stölzel, Sarah E. Fordham, Devi Nandana, Wei-Yu Lin, Helen Blair, Claire Elstob, Hayden L. Bell, Brigitte Mohr, Leo Ruhnke, Desiree Kunadt, Claudia Dill, Daniel Allsop, Rachel Piddock, Emmanouela-Niki Soura, Catherine Park, Mohd Fadly, Thahira Rahman, Abrar Alharbi, Manja Wobus, Heidi Altmann, Christoph Röllig, Lisa Wagenführ, Gail L. Jones, Tobias Menne, Graham H. Jackson, Helen J. Marr, Jude Fitzgibbon, Kenan Onel, Manja Meggendorfer, Amber Robinson, Zuzanna Bziuk, Emily Bowes, Olaf Heidenreich, Torsten Haferlach, Sara Villar, Beñat Ariceta, Rosa Ayala Diaz, Steven J. Altschuler, Lani F. Wu, Felipe Prosper, Pau Montesinos, Joaquin Martinez-Lopez, Martin Bornhäuser, James M. Allan

×

Figure 3

Cells with biallelic TET2 mutations are sensitive to the hypomethylating agent 5′-Aza in in vitro model systems.

Options: View larger image (or click on image) Download as PowerPoint
Cells with biallelic TET2 mutations are sensitive to the hypomethylating...
(A) Parental TET2 monoallelic HEL cell clones (HEL TET2 monoallelic; unfilled symbols) and TET2 CRISPR/Cas9-mutated HEL cell clones (HEL TET2 biallelic; filled symbols) were cultured in soft agar supplemented with 1 μM 5′-Aza (left), 20 nM Ara-C (center), or 20 nM daunorubicin (right), and CE (relative to respective vehicle control–treated cells) was determined after 30 days. Mean and SD of indicated number of clones from 3 independent experiments shown. P values calculated by Student’s t test (2-tailed). (B) Parental TET2 monoallelic HEL cell clones (HEL TET2 monoallelic; unfilled symbols) and TET2 CRISPR/Cas9-mutated HEL cell clones (HEL TET2 biallelic; filled symbols) were treated with 5′-Aza (left), Ara-C (center), or daunorubicin (right), and cell density (relative to respective vehicle control–treated cells) was determined after 96 hours. Data represent mean and SD of indicated number of clones from 3 independent experiments. P values calculated by 2-way ANOVA. (C) Western blot showing cleaved PARP in HEL cells with monoallelic and biallelic TET2 mutations following exposure to 2 mM 5′-Aza over 48 hours. GAPDH was used as a loading control. (D) Western blot (top) showing TET2 protein expression in a panel of 10 AML cell lines. GAPDH was used as a loading control. TET2 protein expression was quantified in each cell line and plotted against 5′-Aza IC50 (left) and IC90 (right) values. AU were measured by the Fuji LAS-300 Image Analyzer.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts