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Overexpression of the anti-apoptotic protein AVEN contributes to increased malignancy in hematopoietic neoplasms

Oncogene volume 32, pages 2586–2591 (2013)Cite this article

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Abstract

AVEN has been identified as an inhibitor of apoptosis, which binds to the adaptor protein, APAF-1, and thereby prevents apoptosome formation and mitochondrial apoptosis. Recent data have demonstrated high expression levels of AVEN messenger RNA in acute leukemias as well as a positive correlation between AVEN mRNA overexpression and poor prognosis in childhood acute lymphoblastic leukemia. On the basis of these data, we investigated the potential involvement of AVEN in tumorigenesis. First, we confirmed the overexpression of AVEN in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) patient samples. We then established a transgenic mouse model with T-cell-specific overexpression of AVEN, with which we demonstrated the oncogenic cooperation of AVEN with heterozygous loss of p53. Finally, we used a subcutaneous xenograft mouse model to show that AVEN knockdown in the T-ALL cell lines, MOLT-4 and CCRF-CEM, and in the acute myeloblastic leukemia cell line, Kasumi-1, leads to a halt in tumor growth owing to the increased apoptosis and decreased proliferation of tumor cells. Collectively, our data demonstrate that the anti-apoptotic molecule, AVEN, functions as an oncoprotein in hematopoietic neoplasms.

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Acknowledgements

The authors would like to thank Susanne Bösser for excellent technical support. This work was supported by grants from the German Cancer Aid Foundation (no. 108659; MZ), the German National Genome Research Network (NGFN project N1KR-S12T23, MZ) and the SFB ‘Lipotox’ of the Austrian Science foundation FWF (no. W30; GH). MZ, IMM and MAR are thankful for the support by the LOEWE Center for Cell and Gene Therapy Frankfurt (HMWK III L 4-518/17.004 (2010)). The Georg-Speyer-Haus is funded jointly by the German Federal Ministry of Health (BMG) and the Ministry of Higher Education, Research and the Arts of the state of Hessen (HMWK).

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Author notes

  1. S B M Fernández

    Present address: 10Current address: Department of Immunology and Oncology, National Center for Biotechnology (CNB)/CSIC, E-28049 Madrid, Spain.,

  2. M Eißmann, I M Melzer, S B M Fernández and G Michel: These authors contributed equally to this work.

  3. Current address: Transgene Facility Charité, Transgenic Technologies Charité, Department of Experimental Medicine (FEM), Krahmerstr. 6, D-12207 Berlin, Germany.

Authors and Affiliations

  1. Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus, Frankfurt, Germany

    M Eißmann, I M Melzer, S B M Fernández, P Finkenwirth, M Grez, N Haetscher, M A Rieger & M Zörnig

  2. German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg/Munich, Germany

    G Michel & M Hrabě de Angelis

  3. Chair for Experimental Genetics, Technische Universität München, Freising-Weihenstephan, Germany

    M Hrabě de Angelis

  4. Institute of Pathology, Medical University of Graz, Graz, Austria

    G Hoefler

  5. Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany

    A Jauch & B Schoell

  6. National Center for Tumor Diseases Heidelberg (NCT), German Cancer Research Center, Heidelberg, Germany

    M Schmidt & C C Bartholomae

  7. Senckenberg Institute of Pathology, Goethe-University Hospital, Frankfurt, Germany

    S Newrzela

  8. Institute of Neurology (Edinger Institute), Frankfurt, Germany

    C Zachskorn & M Mittelbronn

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  1. M Eißmann
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Correspondence to M Zörnig.

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Eißmann, M., Melzer, I., Fernández, S. et al. Overexpression of the anti-apoptotic protein AVEN contributes to increased malignancy in hematopoietic neoplasms. Oncogene 32, 2586–2591 (2013). https://doi.org/10.1038/onc.2012.263

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  • DOI: https://doi.org/10.1038/onc.2012.263

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