1. ¹Department of Hematology and Oncology, Charité, Campus Virchow-Klinikum, University Medicine Berlin, Berlin, Germany
2. ²Max Delbrück Center for Molecular Medicine, Berlin, Germany
3. ³Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany
4. ⁴Institute of Pathology, Charité, Campus Benjamin Franklin, University Medicine Berlin, Berlin, Germany
5. ⁵Institute of Molecular Pharmacology, Berlin, Germany
6. ⁶Department of Cellular and Molecular Immunology, University of Göttingen Medical School, Göttingen, Germany

Correspondence: Dr F Jundt, Department of Hematology and Oncology, University Medicine Berlin, Charité, Campus Virchow-Klinikum, Augustenburger Platz 1, Berlin 13353, Germany. E-mail: fjundt@mdc-berlin.de

⁷These authors contributed equally to this work.

Received 9 November 2007; Revised 12 March 2008; Accepted 19 March 2008; Published online 1 May 2008.

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.