TY - JOUR AU - Stölzel, Friedrich AU - Fordham, Sarah E. AU - Nandana, Devi AU - Lin, Wei-Yu AU - Blair, Helen AU - Elstob, Claire AU - Bell, Hayden L. AU - Mohr, Brigitte AU - Ruhnke, Leo AU - Kunadt, Desiree AU - Dill, Claudia AU - Allsop, Daniel AU - Piddock, Rachel AU - Soura, Emmanouela-Niki AU - Park, Catherine AU - Fadly, Mohd AU - Rahman, Thahira AU - Alharbi, Abrar AU - Wobus, Manja AU - Altmann, Heidi AU - Röllig, Christoph AU - Wagenführ, Lisa AU - Jones, Gail L. AU - Menne, Tobias AU - Jackson, Graham H. AU - Marr, Helen J. AU - Fitzgibbon, Jude AU - Onel, Kenan AU - Meggendorfer, Manja AU - Robinson, Amber AU - Bziuk, Zuzanna AU - Bowes, Emily AU - Heidenreich, Olaf AU - Haferlach, Torsten AU - Villar, Sara AU - Ariceta, Beñat AU - Diaz, Rosa Ayala AU - Altschuler, Steven J. AU - Wu, Lani F. AU - Prosper, Felipe AU - Montesinos, Pau AU - Martinez-Lopez, Joaquin AU - Bornhäuser, Martin AU - Allan, James M. T1 - Biallelic TET2 mutations confer sensitivity to 5′-azacitidine in acute myeloid leukemia PY - 2023/01/24/ AB - 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. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.150368 VL - 8 IS - 2 UR - https://doi.org/10.1172/jci.insight.150368 PB - The American Society for Clinical Investigation ER -