1. Biallelic TET2 mutation sensitizes to 5’-azacitidine in acute myeloid leukemia
- Author
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Stölzel, Friedrich, Fordham, Sarah E, Nandana, Devi, Lin, Wei-Yu, Blair, Helen J, Elstob, Claire J, Bell, Hayden L, Mohr, Brigitte, Ruhnke, Leo, Kunadt, Desiree, Dill, Claudia, Allsop, Daniel A, Piddock, Rachel E, Soura, Emmanouela-Niki, Park, Catherine Vida, Fadly, Mohd, Rahman, Thahira, Alharbi, Abrar A, Wobus, Manja, Altmann, Heidi, Röllig, Christoph, Wagenführ, Lisa, Jones, Gail L, Menne, Tobias, Jackson, Graham H, Marr, Helen J, Fitzgibbon, Jude, Onel, Kenan, Meggendorfer, Manja, Robinson, Amber, Bziuk, Zuzanna, Bowes, Emily, Heidenreich, Olaf, Haferlach, Torsten, Villar, Sara, Ariceta, Beñat, Diaz, Rosa Ayala, Altschuler, Steven J, Wu, Lani, Prosper, Felipe, Montesinos, Pau, Martinez-Lopez, Joaquin, Bornhäuser, Martin, and Allan, James M
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Hematology ,Genetics ,Pediatric ,Pediatric Cancer ,Rare Diseases ,Human Genome ,2.1 Biological and endogenous factors ,Aetiology ,Good Health and Well Being ,Humans ,Mice ,Animals ,Azacitidine ,Leukemia ,Myeloid ,Acute ,Kaplan-Meier Estimate ,Mutation ,DNA-Binding Proteins ,Dioxygenases ,Leukemias ,Molecular genetics ,Biomedical and clinical sciences ,Health sciences - 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.
- Published
- 2023