Biallelic TET2 mutations confer sensitivity to 5'-azacitidine in acute myeloid leukemia
Friedrich Stölzel 1 , Sarah E Fordham 2 , Devi Nandana 2 , Wei-Yu Lin 2 , Helen Blair 2 , Claire Elstob 2 , Hayden L Bell 2 , Brigitte Mohr 1 , Leo Ruhnke 1 , Desiree Kunadt 1 , Claudia Dill 1 , Daniel Allsop 2 , Rachel Piddock 2 , Emmanouela-Niki Soura 2 , Catherine Park 2 , Mohd Fadly 2 , Thahira Rahman 2 , Abrar Alharbi 2 , Manja Wobus 1 , Heidi Altmann 1 , Christoph Röllig 1 , Lisa Wagenführ 1 , Gail L Jones 3 , Tobias Menne 3 , Graham H Jackson 3 , Helen J Marr 3 , Jude Fitzgibbon 4 , Kenan Onel 5 , Manja Meggendorfer 6 , Amber Robinson 2 , Zuzanna Bziuk 2 , Emily Bowes 2 , Olaf Heidenreich 2 , Torsten Haferlach 6 , Sara Villar 7 , Beñat Ariceta 8 9 , Rosa Ayala Diaz 10 , Steven J Altschuler 11 , Lani F Wu 11 , Felipe Prosper 7 , Pau Montesinos 12 , Joaquin Martinez-Lopez 10 , Martin Bornhäuser 1 13 , James M Allan 2
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.
CITATION JCI Insight. 2023 Jan 24;8(2):e150368. doi: 10.1172/jci.insight.150368