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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

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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 4

Cells with biallelic TET2 mutations are subject to 5′-Aza–induced negative selection in an orthotopic AML mouse model.

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Cells with biallelic TET2 mutations are subject to 5′-Aza–induced negati...
(A) Schematic of orthotopic AML mouse model. HEL TET2 monoallelic and HEL TET2 biallelic cell clones were coinjected in a 1:1 ratio into the femurs of Rag2−/−Il2rg−/− mice. Treatment with 5′-Aza (5 mg/kg daily for 5 days) or vehicle control (VC) was initiated on day 28 (postinjection), and animals were euthanized on day 35 for TET2 allele-specific qPCR analysis of harvested tissues. (B) Tissue samples collected from mice were analyzed by custom TET2 allele-specific qPCR assay. Shown are inverse log2 [ΔCt] values, which represent relative expression of the WT versus the 4 bp deleted TET2 allele in individual samples and are the means of triplicate reactions. Inverse log2 [ΔCt] of 1 indicates a 1:1 ratio between the WT and 4 bp deleted TET2 alleles (and hence HEL TET2 monoallelic and HEL TET2 biallelic clones), whereas inverse log2 [ΔCt] > 1 or inverse log2 [ΔCt] < 1 indicates dominance of the WT (HEL TET2 monoallelic) or 4 bp deleted (HEL TET2 biallelic) allele, respectively. Red points indicate samples that were dominated entirely by 1 cell clone. Horizontal dashed lines represent median inverse log2 [ΔCt] values across all samples from VC-treated or 5′-Aza–treated mice. The left panel shows data from all harvested tissues (BM, peripheral blood, spleen, and tumors), and the right panel shows data from BM only. P values comparing inverse log2 [ΔCt] values from VC-treated and 5′-Aza–treated mice were calculated using a Mann-Whitney test.

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