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Clinical impact of GATA2 mutations in acute myeloid leukemia patients harboring CEBPA mutations: a study of the AML study group

Leukemia volume 30, pages 2248–2250 (2016)Cite this article

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Acute myeloid leukemia (AML) with biallelic mutations in the CCAAT/enhancer-binding-protein-alpha gene (CEBPAbi) has now been included in 2016 revision of the World Health Organization classification of myeloid neoplasms as a definite entity due to its association with distinct biological and clinical features as well as its prognostic significance.1 Mutations in CEBPA (CEBPAmut) predominantly occur in AML with normal cytogenetics (~15%), and ~60% of the mutated cases carry biallelic mutations. Several studies concordantly showed that in particular patients with CEBPAbi have a favorable outcome compared with monoallelic mutated or wild-type CEBPA (CEBPAwt) patients.2, 3 Recently, mutations in the transcription factor GATA2 were identified as genetic lesions potentially cooperating with CEBPAbi with a coincidence of 18–41%.4, 5 Both, CEBPA and GATA2, are involved in the control of proliferation and differentiation of myeloid progenitors, and germline mutations in both genes have been found predisposing affected individuals for the development of AML.3, 6 GATA2 knockout mice suffer from severe anemia and die around day 10 of embryonic development.7 Data from functional studies showed that there is an important interplay between the two genes, for example, through direct protein–protein interaction.8 In addition, the C/EBPα-dependent activation of target genes is enhanced through coexpression of GATA2wt. Finally, preliminary data suggest that GATA2mut allow further refinement of CEBPAmut AML patients with regard to their clinical outcome.5

In our study, we evaluated the frequency and the clinical impact of GATA2mut within a large cohort of CEBPAmut AML patients. In total, 202 AML patients (age 18–78 years) with CEBPA single (CEBPAsm, n=89) or CEBPAbi (n=113) mutations were analyzed for the presence of concurrent GATA2mut. All patients were enrolled in one of six AML study group (AMLSG) treatment trials applying intensive therapy (AMLHD93 n=15;9 AMLHD98A (NCT00146120) n=53; AMLHD 98B n=13;10 AMLSG 07-04 (NCT00151242) n=74; AMLSG 06-04 (NCT00151255) n=25 and AMLSG 12-09 (NCT01180322) n=22). The clinical studies were approved by the local ethics review committees and all patients gave informed consent for treatment, molecular analysis and cryopreservation of leukemia samples according to the Declaration of Helsinki. In the AMLHD 98B- and AMLSG 06-04 trials, patients over the age of 60 were enrolled. The AMLSG 12-09 trial had no upper age limit. In the remaining trials, patients 18–60 years of age were eligible. GATA2mut screening was performed using a DNA-based PCR assay covering exons 2–6 followed by Sanger sequencing.4

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References

  1. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127: 2391–2405.

    Article  CAS  Google Scholar 

  2. Wouters BJ, Louwers I, Valk PJ, Löwenberg B, Delwel R . A recurrent in-frame insertion in a CEBPA transactivation domain is a polymorphism rather than a mutation that does not affect gene expression profiling-based clustering of AML. Blood 2007; 109: 389–390.

    Article  CAS  Google Scholar 

  3. Taskesen E, Bullinger L, Corbacioglu A, Sanders MA, Erpelinck CA, Wouters BJ et al. Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity. Blood 2011; 117: 2469–2475.

    Article  CAS  Google Scholar 

  4. Greif PA, Dufour A, Konstandin NP, Ksienzyk B, Zellmeier E, Tizazu B et al. GATA2 zinc finger 1 mutations associated with biallelic CEBPA mutations define a unique genetic entity of acute myeloid leukemia. Blood 2012; 120: 395–403.

    Article  CAS  PubMed  Google Scholar 

  5. Fasan A, Eder C, Haferlach C, Grossmann V, Kohlmann A, Dicker F et al. GATA2 mutations are frequent in intermediate-risk karyotype AML with biallelic CEBPA mutations and are associated with favorable prognosis. Leukemia 2013; 27: 482–485.

    Article  CAS  Google Scholar 

  6. Hahn CN, Chong CE, Carmichael CL, Wilkins EJ, Brautigan PJ, Li XC et al. Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nat Genet 2011; 43: 1012–1017.

    Article  CAS  PubMed  Google Scholar 

  7. Tsai FY, Keller G, Kuo FC, Weiss M, Chen J, Rosenblatt M et al. An early haematopoietic defect in mice lacking the transcription factor GATA-2. Nature 1994; 371: 221–226.

    Article  CAS  PubMed  Google Scholar 

  8. Tong Q, Tsai J, Tan G, Dalgin G, Hotamisligil GS . Interaction between GATA and the C/EBP family of transcription factors is critical in GATA-mediated suppression of adipocyte differentiation. Mol Cell Biol 2005; 25: 706–715.

    Article  CAS  PubMed  Google Scholar 

  9. Schlenk RF, Benner A, Hartmann F, del Valle F, Weber C, Fischer JT et al. Risk-adapted postremission therapy in acute myeloid leukemia: results of the German Multicenter AML HD93 treatment trial. Leukemia 2003; 17: 1521–1528.

    Article  CAS  Google Scholar 

  10. Schlenk RF, Fröhling S, Hartmann F, Fischer JT, Glasmacher A, del Valle F et al. Phase III study of all-trans retinoic acid in previously untreated patients 61 years or older with acute myeloid leukemia. Leukemia 2004; 18: 1798–1803.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by grants from the Deutsche Krebshilfe (no.109675).

Author contributions

Conception and design: Frauke Theis and Konstanze Döhner. Provision of study materials or patients: Frauke Theis, Andrea Corbacioglu, Verena I Gaidzik, Peter Paschka, Lars Bullinger, Michael Heuser, Arnold Ganser, Felicitas Thol, Brigitte Schlegelberger, Gudrun Göhring, Claus-Henning Köhne, Ulrich Germing, Peter Brossart, Heinz-August Horst, Detlef Haase, Katharina Götze, Mark Ringhoffer, Walter Fiedler, David Nachbaur, Thomas Kindler, Gerhard Held, Michael Lübbert, Mohammed Wattad, Helmut R Salih, Jürgen Krauter, Hartmut Döhner, Richard F Schlenk and Konstanze Döhner. Collection and assembly of data: Richard F Schlenk, Daniela Weber, Frauke Theis and Konstanze Döhner. Data analysis and interpretation: Richard F Schlenk, Daniela Weber, Frauke Theis, Hartmut Döhner and Konstanze Döhner. Manuscript writing: Frauke Theis and Konstanze Döhner. Final approval of manuscript: Frauke Theis, Andrea Corbacioglu, Verena I Gaidzik, Peter Paschka, Daniela Weber, Lars Bullinger, Michael Heuser, Arnold Ganser, Felicitas Thol, Brigitte Schlegelberger, Gudrun Göhring, Claus-Henning Köhne, Ulrich Germing, Peter Brossart, Heinz-August Horst, Detlef Haase, Katharina Götze, Mark Ringhoffer, Walter Fiedler, David Nachbaur, Thomas Kindler, Gerhard Held, Michael Lübbert, Mohammed Wattad, Helmut R Salih, Jürgen Krauter, Hartmut Döhner, Richard F Schlenk and Konstanze Döhner.

Author information

Authors and Affiliations

  1. Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany

    F Theis, A Corbacioglu, V I Gaidzik, P Paschka, D Weber, L Bullinger, H Döhner, R F Schlenk & K Döhner

  2. Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany

    M Heuser, A Ganser & F Thol

  3. Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany

    B Schlegelberger & G Göhring

  4. Department of Oncology and Hematology, Klinikum Oldenburg, Oldenburg, Germany

    C-H Köhne

  5. Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany

    U Germing

  6. Department of Internal Medicine III, University Hospital of Bonn, Bonn, Germany

    P Brossart

  7. Department of Internal Medicine II, University Hospital Schleswig-Holstein Kiel, Kiel, Germany

    H-A Horst

  8. Department of Hematology and Oncology, University Hospital of Göttingen, Göttingen, Germany

    D Haase

  9. Department of Internal Medicine III, University Hospital of Munich, Munich, Germany

    K Götze

  10. Department of Internal Medicine III, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany

    M Ringhoffer

  11. Department of Oncology and Hematology, Hubertus Wald University Cancer Center, University Medical Center Eppendorf, Hamburg, Germany

    W Fiedler

  12. Internal Medicine V, University Hospital of Innsbruck, Innsbruck, Austria

    D Nachbaur

  13. Third Department of Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany

    T Kindler

  14. Department of Internal Medicine I, University Hospital of Saarland, Homburg, Germany

    G Held

  15. Department of Medicine, Division of Hematology and Oncology, University Hospital of Freiburg, Freiburg, Germany

    M Lübbert

  16. Department of Hematology and Oncology, Kliniken Essen Süd, Essen, Germany

    M Wattad

  17. Department of Hematology and Oncology, Eberhard Karls-University, Tübingen, Germany

    H R Salih

  18. Department of Internal Medicine III, Städtisches Klinikum Braunschweig, Braunschweig, Germany

    J Krauter

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  1. F Theis
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  2. A Corbacioglu
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Corresponding author

Correspondence to K Döhner.

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The authors declare no conflict of interest.

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Theis, F., Corbacioglu, A., Gaidzik, V. et al. Clinical impact of GATA2 mutations in acute myeloid leukemia patients harboring CEBPA mutations: a study of the AML study group. Leukemia 30, 2248–2250 (2016). https://doi.org/10.1038/leu.2016.185

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