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Loss of B cell identity correlates with loss of B cell-specific transcription factors in Hodgkin/Reed-Sternberg cells of classical Hodgkin lymphoma

Oncogene volume 21, pages 4908–4920 (2002)Cite this article

Abstract

In classical Hodgkin lymphoma the malignant Hodgkin/Reed-Sternberg (HRS) cells characteristically constitute only a small minority of the tumour load. Their origin has been debated for decades, but on the basis of rearrangement and somatic hypermutations of their immunoglubulin (Ig) genes, HRS cells are now ascribed to the B-cell lineage. Nevertheless, phenotypically HRS cells have lost their B cell identity: they usually lack common B cell-specific surface markers such as CD19 and CD79a as well as Ig gene transcripts. Here we demonstrate that Ig promoters as well as both intronic and 3′ enhancer sequences are transcriptionally inactive in HRS cell lines. This inactivity correlates with either reduced levels or even a complete lack of several B cell-specific transcription factors required for their expression: Oct-2, OBF-1, PU.1, E47/E12, PAX-5 and EBF. Moreover, we demonstrate that PU.1 and PAX-5 are significantly down-regulated in HRS cells in pathological specimens from primary tumour tissues. However, forced expression of these transcription factors can activate regulatory sequences of silenced B cell marker genes, and in one instance also transcription from a silenced endogenous locus. Thus, HRS cells are dedifferentiated B cells with global down-regulation of B cell-specific genes.

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Acknowledgements

We are grateful to the following for making agents available to us: Meinrad Busslinger, Rudi Grosschedl, Sola Kim, Claus Nerlov, Tanja X Pedersen, Sven Pettersson, Claus Scheidereit and Dan Tenen. Our special thanks to Patrick Matthias and Mikael Sigvardsson for their generous supplies of material, and to Patrick Matthias for his critical comments on the manuscript. Thanks to Bjarne J. Bonven for being a constant source of inspiration. We also acknowledge the proficient technical assistance of Margaret Gellett and Maria Jakobsen. This work was supported by grants to S Junker from the Danish Cancer Society, Karen Elise Jensen Foundation, Danish Cancer Research Foundation, NOVO Nordic Foundation, Eva & Henry Frænkel Memorial Foundation and the AP Møller Foundation for the Advancement of Medical Sciences.

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  1. Institute of Human Genetics, University of Aarhus, Aarhus C, DK-8000, Denmark

    Christina B Hertel & Steffen Junker

  2. Institute of Pathology, Aarhus University Hospital, Aarhus C, DK-8000, Denmark

    Xiao-ge Zhou & Stephen J Hamilton-Dutoit

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  1. Christina B Hertel
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Correspondence to Steffen Junker.

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Hertel, C., Zhou, Xg., Hamilton-Dutoit, S. et al. Loss of B cell identity correlates with loss of B cell-specific transcription factors in Hodgkin/Reed-Sternberg cells of classical Hodgkin lymphoma. Oncogene 21, 4908–4920 (2002). https://doi.org/10.1038/sj.onc.1205629

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