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Expression of BARHL1 in medulloblastoma is associated with prolonged survival in mice and humans

Oncogene volume 30, pages 4721–4730 (2011)Cite this article

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Abstract

Medulloblastoma is the most common malignant brain tumor in childhood, and development of targeted therapies is highly desired. Although the molecular mechanisms of malignant transformation are not fully understood, it is known that medulloblastomas may arise from cerebellar granule neuron precursors. The homeodomain transcription factor Barhl1 is known to regulate migration and survival of granule cell precursors, but its functional role in medulloblastoma is unknown. We show here that the expression of BARHL1 is significantly upregulated during human cerebellar development and in human medulloblastoma samples as compared with the normal adult cerebellum. We also detected high levels of Barhl1 expression in medulloblastomas of Math1-cre:SmoM2 mice, a mouse model for Sonic hedgehog-associated medulloblastomas that we developed previously. To investigate Barhl1 function in vivo during tumor development, we generated Barhl1−/−Math1-cre:SmoM2 mice. Interestingly, tumors that developed in these mice displayed increased mitotic activity and decreased neuronal differentiation. Moreover, survival of these mice was significantly decreased. Similarly, low expression of BARHL1 in human medulloblastoma cases was associated with a less favorable prognosis for patients. These results suggest that the expression of Barhl1 decelerates tumor growth both in human and in murine medulloblastomas and should be further investigated with respect to potential implications for individualized therapeutic strategies.

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Acknowledgements

We are indebted to Michael Schmidt, Veronika Kaltenbrunn, Dagmar Metzger, Philipp Neumann and Silvia Occhionero for excellent technical support, to Dr Mehdi Shakarami and Dr Stefanie Ohlemeyer for animal husbandry. We acknowledge Dr Rosalind Segal for providing Zic antibodies. This work was supported by grants from the Wilhelm-Sander-Stiftung and the Friedrich-Baur-Stiftung (all to US). US is a member of the Max-Eder-junior-research-program of the German Cancer Aid. The HIT-trial-office at the University Medical Center Hamburg-Eppendorf is supported by the German Children's Cancer Foundation (Deutsche Kinderkrebsstiftung) and by the Fördergemeinschaft Kinderkrebszentrum Hamburg e.V.

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Authors and Affiliations

  1. Center for Neuropathology, Ludwig-Maximilians-University, Munich, Germany

    J Pöschl, A Lorenz, J Herms, H A Kretzschmar & U Schüller

  2. Department of Pathology, University of Bonn Medical Center, Bonn, Germany

    W Hartmann

  3. Department of Pediatric Hematology and Oncology, University Medical Center, Hamburg-Eppendorf, Germany

    A O von Bueren & S Rutkowski

  4. Department of Human Genetics, Academic Medical Center, Amsterdam, The Netherlands

    M Kool

  5. Center for Advanced Biotechnology and Medicine and Department of Pediatrics, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, NJ, USA

    S Li & M Xiang

  6. Department of Neurosurgery, Ludwig-Maximilians-University, Munich, Germany

    A Peraud & J-C Tonn

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  1. J Pöschl
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  10. M Xiang
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Correspondence to U Schüller.

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Pöschl, J., Lorenz, A., Hartmann, W. et al. Expression of BARHL1 in medulloblastoma is associated with prolonged survival in mice and humans. Oncogene 30, 4721–4730 (2011). https://doi.org/10.1038/onc.2011.173

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