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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

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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.

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Acknowledgments

This work was supported by grants from the EORTC (EGAM 2009 NOCI), the EORTC Charitable Trust, and the Netherlands Institute for Regenerative Medicine (NIRM).

Authors’ contributions

MGA, 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.

Conflicts of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Nijmegen Medical Center, Geert Grooteplein zuid 8, 6525 GA, Nijmegen, The Netherlands

    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, Bert A. van der Reijden & Joop H. Jansen

  2. Faculdade de Medicina da Universidade do Porto, Porto, Portugal

    Pedro da Silva-Coelho

  3. Department of Hematology and Clinical & Biological Sciences, S Luigi Hospital, University of Turin, Turin, Italy

    Daniela Cilloni & Giuseppe Saglio

  4. Department of Hematology and Tumor Bank, Saint-Antoine Hospital, AP-HP and University Pierre and Marie Curie, Paris, France

    Jean-Pierre Marie & Ruoping Tang

  5. Department of Hematology and Clinical Institute of Laboratory Diagnosis, University School of Medicine, Zagreb, Croatia

    Boris Labar

  6. Department of Hematology, Tor Vergata University Hospital, Rome, Italy

    Sergio Amadori

  7. Department of Hematology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    Petra Muus

  8. Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands

    Roel Willemze & Erik W. A. Marijt

  9. Department of Tumor Immunology, Radboudumc, Nijmegen, The Netherlands

    Theo de Witte

  10. European Organization for Research and Treatment of Cancer (EORTC) Headquarters, Brussels, Belgium

    Stefan Suciu

Authors
  1. Mariam G. Aslanyan
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  2. Leonie I. Kroeze
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  3. Saskia M. C. Langemeijer
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Correspondence to Stefan Suciu or Joop H. Jansen.

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Aslanyan, M.G., Kroeze, L.I., Langemeijer, S.M.C. et al. Clinical and biological impact of TET2 mutations and expression in younger adult AML patients treated within the EORTC/GIMEMA AML-12 clinical trial. Ann Hematol 93, 1401–1412 (2014). https://doi.org/10.1007/s00277-014-2055-7

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