Annals of Hematology

, Volume 93, Issue 8, pp 1401–1412

Clinical and biological impact of TET2 mutations and expression in younger adult AML patients treated within the EORTC/GIMEMA AML-12 clinical trial

  • Mariam G. Aslanyan
  • Leonie I. Kroeze
  • Saskia M. C. Langemeijer
  • Theresia N. Koorenhof-Scheele
  • Marion Massop
  • Patricia van Hoogen
  • Ellen Stevens-Linders
  • Louis T. van de Locht
  • Evelyn Tönnissen
  • Adrian van der Heijden
  • Pedro da Silva-Coelho
  • Daniela Cilloni
  • Giuseppe Saglio
  • Jean-Pierre 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
Original Article

DOI: 10.1007/s00277-014-2055-7

Cite this article as:
Aslanyan, M.G., Kroeze, L.I., Langemeijer, S.M.C. et al. Ann Hematol (2014) 93: 1401. doi:10.1007/s00277-014-2055-7

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.

Keywords

TET2 mutationsAcute myeloid leukemiaTET2 expressionPrognosis

Supplementary material

277_2014_2055_MOESM1_ESM.docx (636 kb)
ESM 1(DOCX 636 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Mariam G. Aslanyan
    • 1
  • Leonie I. Kroeze
    • 1
  • Saskia M. C. Langemeijer
    • 1
  • Theresia N. Koorenhof-Scheele
    • 1
  • Marion Massop
    • 1
  • Patricia van Hoogen
    • 1
  • Ellen Stevens-Linders
    • 1
  • Louis T. van de Locht
    • 1
  • Evelyn Tönnissen
    • 1
  • Adrian van der Heijden
    • 1
  • Pedro da Silva-Coelho
    • 1
    • 2
  • Daniela Cilloni
    • 3
  • Giuseppe Saglio
    • 3
  • Jean-Pierre Marie
    • 4
  • Ruoping Tang
    • 4
  • Boris Labar
    • 5
  • Sergio Amadori
    • 6
  • Petra Muus
    • 7
  • Roel Willemze
    • 8
  • Erik W. A. Marijt
    • 8
  • Theo de Witte
    • 9
  • Bert A. van der Reijden
    • 1
  • Stefan Suciu
    • 10
  • Joop H. Jansen
    • 1
  1. 1.Department of Laboratory Medicine, Laboratory of HematologyRadboud University Nijmegen Medical CenterNijmegenThe Netherlands
  2. 2.Faculdade de Medicina da Universidade do PortoPortoPortugal
  3. 3.Department of Hematology and Clinical & Biological Sciences, S Luigi HospitalUniversity of TurinTurinItaly
  4. 4.Department of Hematology and Tumor Bank, Saint-Antoine HospitalAP-HP and University Pierre and Marie CurieParisFrance
  5. 5.Department of Hematology and Clinical Institute of Laboratory DiagnosisUniversity School of MedicineZagrebCroatia
  6. 6.Department of HematologyTor Vergata University HospitalRomeItaly
  7. 7.Department of HematologyRadboud University Nijmegen Medical CenterNijmegenThe Netherlands
  8. 8.Department of HematologyLeiden University Medical CenterLeidenThe Netherlands
  9. 9.Department of Tumor ImmunologyRadboudumcNijmegenThe Netherlands
  10. 10.European Organization for Research and Treatment of Cancer (EORTC) HeadquartersBrusselsBelgium