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Incidence and Clinical Impact of TET2 Mutations in Acute Myeloid Leukemia Patients Treated within the EORTC/GIMEMA AML-12/06991 AML Trial

Defining specific subgroups within AML based on cytogenetic and molecular markers is crucial for diagnostic and prognostic purposes, as well as for adequate therapeutic decisions. Recently, we and others have reported mutations in a novel gene, TET2, that occur in a broad spectrum of myeloid neoplasms. Recent publications regarding the function of the TET protein family members implicate that these proteins play a role in epigenetic regulation of gene expression through DNA methylation, a process known to be disturbed in several hematological malignancies. Thus far, TET2 represents the most frequently mutated gene in myelodysplastic syndromes (26%), and mutations are also frequent in myeloproliferative disorders (12%), mastocytosis (30%), acute myeloid leukemia (10%) and chronic myelomonocytic leukemia (22%). The aim of this study was to define the incidence and clinical impact of TET2 mutations in acute myeloid leukemia patients who were treated uniformously within a defined clinical trial. In addition, we measured the mRNA levels of TET2 in patients with and without TET2 mutations, in order to establish whether the TET2 expression levels might correlate with clinical outcome. We performed direct DNA and/or RNA sequencing of the TET2 gene for mutation analysis and Q-PCR to measure mRNA expression levels. A cohort of up to 400 AML patients that was treated within the EORTC/GIMEMA AML-12/06991 trial was screened. In this trial newly diagnosed patients with AML between 15 and 60 years of age were included, with the exception of patients with acute promyelocytic leukemia. TET2 mutations were detected in 9% of the cases. Mutations were scattered along the whole coding region of the TET2 gene. In 12% of the cases, this led to a premature stop codon, in 24% to a frameshift and premature truncation of the reading frame, and in 60% to missense substitutions, clustering within the two conserved box 1 and box 2 regions of the TET2 gene. In one patient, a splice site mutation was found. TET2 mutations often co-occurred with other well-known mutations, including mutations in the nucleophosmin gene (NPM1), mutations of the fms-like tyrosine kinase 3 (FLT3), and the mixed lineage leukemia gene (MLL). Truncations in the TET2 gene co-occurred most frequently with mutations of NPM1 and FLT3. To determine the clinical significance of TET2 mutations, overall survival of TET2 mutated versus TET2 wild type patients was assessed. Analysis based on the first 224 AML patients showed a clear trend towards poor prognosis of patients carrying a TET2 mutation (p=0.065). So far, TET2 expression levels do not seem to correlate with clinical outcome. The multivariate analysis of the whole cohort will be presented. We conclude that TET2 represents a novel genetic marker that is mutated in approximately 10% of the cases of de novo AML and that in this patient category, mutation of TET2 correlates with poor clinical outcome.

TET2; Mutations; Acute Myeloid Leukemia; Clinical impact

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