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Clinical and biological impact of TET2 mutations and expression in younger adult AML patients treated within the EORTC/GIMEMA AML-12 clinical trial.
- Source :
-
Annals of hematology [Ann Hematol] 2014 Aug; Vol. 93 (8), pp. 1401-12. Date of Electronic Publication: 2014 Mar 29. - Publication Year :
- 2014
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1432-0584
- Volume :
- 93
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Annals of hematology
- Publication Type :
- Academic Journal
- Accession number :
- 24994606
- Full Text :
- https://doi.org/10.1007/s00277-014-2055-7