TET2 mutations in cytogenetically normal acute myeloid leukemia: clinical implications and evolutionary patterns.

Mutations of the Ten-Eleven-Translocation 2 (TET2) gene have been identified in patients with various myeloid neoplasms, but the clinical relevance of these mutations and their timing during disease development in cytogenetically normal acute myeloid leukemia (CN-AML) remain unclear. The total coding region of TET2 was analyzed by direct sequencing in 215 CN-AML patients younger than 60 years from multicenter treatment trials AML-SHG 0199 (ClinicalTrials Identifier NCT00209833) and 0295. Associations were analyzed in the context of other molecular markers, such as CEBPA, DNMT3A, NMP1, FLT3, IDH1/2, RAS, and WT1. To investigate the order of appearance of TET2 and concomitant mutations, targeted deep resequencing was performed in six patients. At least one sequence variation with impact on TET2 protein sequence was found in 13 of the 215 CN-AML patients (6%). Patients with TET2 mutations tended to be older (P = 0.078) and had higher platelet counts (P = 0.041). TET2-mutated patients were more likely to have concomitant NPM1 (11 of 13; P = 0.047) and DNMT3A (10 of 13; P = 0.001) mutations but were mutually exclusive to partial tandem duplication of the MLL gene (MLL-PTD) and IDH1/2 mutations. TET2 mutations were identified as subclones in four of the six investigated patients by deep sequencing. Progenitor-derived colony assays suggest a stepwise acquisition of mutations during disease development, TET2 mutation being later than NPM1 and DNMT3A. The TET2 mutation status did not influence overall or relapse-free survival.