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 6

ABCB1 affects sensitivity to 5′-Aza in HEL AML cells.

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ABCB1 affects sensitivity to 5′-Aza in HEL AML cells. (A) Mean synergy s...
(A) Mean synergy scores for verapamil and 5′-Aza combination and for (B) tariquidar and 5′-Aza in combination, stratified by TET2 mutant allele dosage. Synergy scores for verapamil/5′-Aza and tariquidar/5′-Aza were significantly higher for TET2 monoallelic mutant HEL cell clones compared with TET2 biallelic HEL cell clones (P = 0.0003 and P < 0.0001, respectively, paired 2-tailed Student’s t test). Data are derived from 6 independent experimental replicates using 2 independent cell clones for each TET2 genotype. Data represent the mean and SD of indicated number of clones. (C) HEL AML cell clones were exposed to escalating doses of 5′-Aza to generate significantly resistant subclones (P = 0.0008, unpaired 2-tailed Student’s t test). Data show IC50 values for 5′-Aza–resistant subclones derived from parental cells with either TET2 monoallelic mutation (unfilled symbols) or TET2 biallelic mutation (filled symbols). Data represent the mean and SD of indicated number of clones. (D) Western blots show ABCB1 protein levels in 3 representative 5′-Aza–resistant derivatives from cells with either TET2 monoallelic mutation (left) or TET2 biallelic mutation (right). (E) ABCB1 protein levels were quantified in parental HEL cells, and 9 independent 5′-Aza–resistant derivatives with either TET2 monoallelic mutation (unfilled symbols) or TET2 biallelic mutation (filled symbols). ABCB1 protein levels were quantified and normalized to GAPDH, with the expression in each parental cell given a nominal value of 1. ABCB1 protein levels of 5′-Aza–resistant derivatives were significantly higher than their respective parental cells (P = 0.0069, paired 2-tailed Student’s t test). Solid horizontal line represents the median fold change in ABCB1 protein expression in 5′-Aza–resistant subclones relative to their respective parental cells (represented by the dashed horizontal line).