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.
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Research Article Hematology

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

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

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Figure 7

Somatic mutations affecting the TET2 locus in AML patients with cytogenetic abnormality of chromosome 4 and response to treatment in AML patients with TET2 mutation.

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Somatic mutations affecting the TET2 locus in AML patients with cytogene...
(A) Illustrated are regions of copy number gain (green), gain with concomitant LOH (blue), and loss (orange) affecting chromosome 4 (discerned using high-density SNP array) in 18 AML patients with cytogenetically detectable abnormalities of chromosome 4. Base substitution mutations (indicated by black triangles) were determined by TET2 exon sequencing. The vertical dashed red line indicates the location of the TET2 gene. The mutation statuses of the 7 patients with loss-of-function TET2 mutations are indicated to the right. Patient ID numbers are shown in parentheses for these patients. (B) Swimmer plots showing patients with TET2-mutated AML treated with either 5′-Aza (left) or low-dose Ara-C plus fludarabine (FLUGA) (right). The AML index case (UPN01) is included in the 5′-Aza swimmer plot for reference. Patients with biallelic TET2 mutation (UPN01, UPN31, UPN33, UPN47, UPN68, UPN73, and UPN78) are represented by purple bars. All other patients had monoallelic TET2 mutation discerned by whole-exome sequencing and are represented by pale yellow bars. European LeukemiaNet (ELN) favorable-, intermediate-, and adverse-risk groups are represented by green, blue, and red squares, respectively. ECOG, Eastern Cooperative Oncology Group performance score.