title: Clinical and biological impact of TET2 mutations and expression in younger adult AML patients treated within the EORTC/GIMEMA AML-12 clinical trial.
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.
authors.affiliation: Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Nijmegen Medical Center, Geert Grooteplein zuid 8, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Mariam G
authors.initials: MG
authors.lastname: Aslanyan
authors.forename: Leonie I
authors.initials: LI
authors.lastname: Kroeze
authors.forename: Saskia M C
authors.initials: SM
authors.lastname: Langemeijer
authors.forename: Theresia N
authors.initials: TN
authors.lastname: Koorenhof-Scheele
authors.forename: Marion
authors.initials: M
authors.lastname: Massop
authors.forename: Patricia
authors.initials: P
authors.lastname: van Hoogen
authors.forename: Ellen
authors.initials: E
authors.lastname: Stevens-Linders
authors.forename: Louis T
authors.initials: LT
authors.lastname: van de Locht
authors.forename: Evelyn
authors.initials: E
authors.lastname: Tönnissen
authors.forename: Adrian
authors.initials: A
authors.lastname: van der Heijden
authors.forename: Pedro
authors.initials: P
authors.lastname: da Silva-Coelho
authors.forename: Daniela
authors.initials: D
authors.lastname: Cilloni
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Saglio
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Marie
authors.forename: Ruoping
authors.initials: R
authors.lastname: Tang
authors.forename: Boris
authors.initials: B
authors.lastname: Labar
authors.forename: Sergio
authors.initials: S
authors.lastname: Amadori
authors.forename: Petra
authors.initials: P
authors.lastname: Muus
authors.forename: Roel
authors.initials: R
authors.lastname: Willemze
authors.forename: Erik W A
authors.initials: EW
authors.lastname: Marijt
authors.forename: Theo
authors.initials: T
authors.lastname: de Witte
authors.forename: Bert A
authors.initials: BA
authors.lastname: van der Reijden
authors.forename: Stefan
authors.initials: S
authors.lastname: Suciu
authors.forename: Joop H
authors.initials: JH
authors.lastname: Jansen
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000293:Adolescent; D000328:Adult; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D002986:Clinical Trials as Topic; D003596:Cytosine / Q000031:analogs & derivatives / Q000032:analysis; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D049308:Dioxygenases; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D015337:Multicenter Studies as Topic; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D011379:Prognosis; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; C000717967:DNMT3A protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011993:Recombinant Fusion Proteins; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D049308:Dioxygenases; C541081:TET2 protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A