Authors: Mariam G Aslanyan Leonie I Kroeze Saskia M C Langemeijer Theresia N KoorenhofScheele Marion Massop Patricia van Hoogen Ellen StevensLinders Louis T van de Locht Evelyn Tönnissen Adrian van der Heijden Pedro da SilvaCoelho Daniela Cilloni Giuseppe Saglio JeanPierre Marie Ruoping Tang Boris Labar Sergio Amadori Petra Muus Roel Willemze Erik W A Marijt Theo de Witte Bert A van der Reijden Stefan Suciu Joop H Jansen
Publish Date: 2014/03/29
Volume: 93, Issue: 8, Pages: 1401-1412
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 AML12 06991 clinical trial In addition the cooccurrence with other genetic defects and the functional consequences of TET2 mutations were investigated TET2 mutations occurred in 76 of the patients and were an independent marker of poor prognosis p = 0024 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 5hydroxymethylcytosine formation In addition we now show that mutant TET2 forms did not act in a dominant negative manner when coexpressed with the wildtype protein Finally as lossoffunction 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 survivalMGA LIK SMCL TNKS MM PvH ESL LvdL ET AvdH PSC performed experiments analyzed and interpreted data DC GS JPM RT BL SA PM RW EWAM TdW recruited patients provided essential patient material and analyzed patient data SS performed statistical analyses MGA BvdR and JHJ designed the study MGA and JHJ wrote the paper All authors have read and approved the manuscript
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