1. Clinical and biological impact of TET2 mutations and expression in younger adult AML patients treated within the EORTC/GIMEMA AML-12 clinical trial.
- Author
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Aslanyan MG, Kroeze LI, Langemeijer SM, Koorenhof-Scheele TN, Massop M, van Hoogen P, Stevens-Linders E, van de Locht LT, Tönnissen E, van der Heijden A, da Silva-Coelho P, Cilloni D, Saglio G, Marie JP, Tang R, Labar B, Amadori S, Muus P, Willemze R, Marijt EW, de Witte T, van der Reijden BA, Suciu S, and Jansen JH
- Subjects
- 5-Methylcytosine analogs & derivatives, Adolescent, Adult, Animals, COS Cells, Chlorocebus aethiops, Clinical Trials as Topic, Cytosine analogs & derivatives, Cytosine analysis, DNA (Cytosine-5-)-Methyltransferases genetics, DNA Methyltransferase 3A, DNA-Binding Proteins biosynthesis, DNA-Binding Proteins physiology, Dioxygenases, Female, Humans, Isocitrate Dehydrogenase genetics, Kaplan-Meier Estimate, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute mortality, Male, Multicenter Studies as Topic, Neoplasm Proteins biosynthesis, Neoplasm Proteins physiology, Prognosis, Prospective Studies, Proto-Oncogene Proteins biosynthesis, Proto-Oncogene Proteins physiology, RNA, Messenger biosynthesis, RNA, Neoplasm biosynthesis, Recombinant Fusion Proteins metabolism, Transfection, Young Adult, DNA-Binding Proteins genetics, Gene Expression Regulation, Leukemic, Leukemia, Myeloid, Acute genetics, Mutation, Neoplasm Proteins genetics, Proto-Oncogene Proteins genetics
- Abstract
We assessed the prognostic impact of TET2 mutations and mRNA expression in a prospective cohort of 357 adult AML patients < 60 years of age enrolled in the European Organization For Research and Treatment of Cancer (EORTC)/Gruppo Italiano Malattie Ematologiche dell' Adulto (GIMEMA) AML-12 06991 clinical trial. In addition the co-occurrence with other genetic defects and the functional consequences of TET2 mutations were investigated. TET2 mutations occurred in 7.6 % of the patients and were an independent marker of poor prognosis (p = 0.024). TET2 and IDH1/2 mutations strongly associated with aberrations in the DNA methyltransferase DNMT3A. Functional studies confirmed previous work that neither nonsense truncations, nor missense TET2 mutations, induced 5-hydroxymethylcytosine formation. In addition, we now show that mutant TET2 forms did not act in a dominant negative manner when co-expressed with the wild-type protein. Finally, as loss-of-function TET2 mutations predicted poor outcome, we questioned whether low TET2 mRNA expression in cases of AML without TET2 mutations would affect overall survival. Notably, also AML patients with low TET2 mRNA expression levels showed inferior overall survival.
- Published
- 2014
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