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Lymphoma

Aberrant expression of Notch1 interferes with the B-lymphoid phenotype of neoplastic B cells in classical Hodgkin lymphoma

Leukemia volume 22, pages 1587–1594 (2008)Cite this article

Abstract

Plasticity of committed mouse B cells has been demonstrated by inactivation of the B-cell commitment transcription factor PAX5, resulting in loss of the B-cell phenotype and differentiation into various hematopoietic lineages. Furthermore, mature mouse B cells could be reprogrammed into macrophages by overexpression of myeloid-specific transcription factors. Here, we report that aberrant activity of the transmembrane receptor, Notch1, interferes with the B-lymphoid phenotype of mature human germinal center-derived B cells in Hodgkin lymphoma, so called Hodgkin and Reed–Sternberg cells. They have lost the B-cell phenotype despite their mature B-cell origin. Notch1 remodels the B-cell transcription factor network by antagonizing the key transcription factors E2A and early B-cell factor (EBF). Through this mechanism, B lineage-specific genes were suppressed and B lineage-inappropriate genes were induced. We provide evidence that absence of the Notch inhibitor Deltex1 contributes to deregulated Notch activity in Hodgkin and Reed–Sternberg cells. These data suggest that Notch activation interferes with dedifferentiation of neoplastic B cells in Hodgkin lymphoma.

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Acknowledgements

We thank Lucio Miele (Maywood, USA) for siRNA sequences for Notch1 and for critical reading of the manuscript; Hans-Martin Jäck (Erlangen, Germany) for advice and discussions and Katharina Kley, Sylvia Wowro, Sandra Meier and Antje Wollny for excellent technical assistance. This work was supported by grants of the Deutsche Forschungsgemeinschaft (Klinische Forschergruppe KFO 105) and the Wilhelm Sander Stiftung (2003.129.2).

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Author notes

  1. F Jundt and Ö Acikgöz: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology and Oncology, Charité, Campus Virchow-Klinikum, University Medicine Berlin, Berlin, Germany

    F Jundt, Ö Acikgöz, R Schwarzer, S Mathas & B Dörken

  2. Max Delbrück Center for Molecular Medicine, Berlin, Germany

    F Jundt, Ö Acikgöz, S Mathas & B Dörken

  3. Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany

    S-H Kwon & H M Reichardt

  4. Institute of Pathology, Charité, Campus Benjamin Franklin, University Medicine Berlin, Berlin, Germany

    I Anagnostopoulos, M Hummel & H Stein

  5. Institute of Molecular Pharmacology, Berlin, Germany

    B Wiesner

  6. Department of Cellular and Molecular Immunology, University of Göttingen Medical School, Göttingen, Germany

    H M Reichardt

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  1. F Jundt
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Correspondence to F Jundt.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Jundt, F., Acikgöz, Ö., Kwon, SH. et al. Aberrant expression of Notch1 interferes with the B-lymphoid phenotype of neoplastic B cells in classical Hodgkin lymphoma. Leukemia 22, 1587–1594 (2008). https://doi.org/10.1038/leu.2008.101

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