TET2 mutations in Acute Myeloid Leukemia (AML): Results from a comprehensive genetic and clinical analysis of the AML study group

Purpose: The tet oncogene family member 2 (TET2) gene was recently identified to be mutated in myeloid disorders including acute myeloid leukemia (AML). To date, there is increasing evidence for a functional role of TET2 mutations (TET2 ^mut) in AML. Thus, we explored the frequency, gene-expression pattern, and clinical impact of TET2 ^mut in a large cohort of patients with AML in the context of other AML-associated aberrations. Patients and Methods: Samples from 783 younger adult patients with AML were analyzed for the presence of TET2 ^mut (coding exons 3 to 11), and results were correlated with data from molecular genetic analyses, gene-expression profiling, and clinical outcome. Results: In total, 66 TET2 ^mut were found in 60 patients (60 of 783 patients; 7.6%), including missense (n = 37), frameshift (n = 16), and nonsense (n = 13) mutations, which, with one exception, were all heterozygous. TET2 ^mut were not correlated with distinct clinical features or genetic alterations, except for isocitrate dehydrogenase mutations (IDH ^mut) that were almost mutually exclusive with TET2mut (P < .001). TET2 ^mut were characterized by only a weak gene-expression pattern, which, nevertheless, reflected TET2 ^mut-associated biology. TET2 ^mut did not impact the response to induction therapy and clinical outcome; the combination of patients who exhibited TET2 ^mut and/or IDH ^mut revealed shorter overall survival (P = .03), although this association was not independent from known risk factors. Conclusion: TET2 ^mut were identified in 7.6% of younger adult patients with AML and did not impact the response to therapy and survival. Mutations were mutually exclusive with IDH ^mut, which supported recent data on a common mechanism of action that might obscure the impact of TET2 ^mut if compared against all other patients with AML.