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Researchers at the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch (Germany) and the Charité University Medicine Berlin (Campus Virchow and Campus Buch) have discovered a molecular mechanism which explains why the cells of Hodgkin lymphoma, a malignancy affecting the lymph nodes, can change their appearance and take on characteristics of other cell lineages. "This is a perfect example of the ability of the B cells, a specific type of human immune cells affected by Hodgkin lymphoma, to be able to modify their differentiation program", say Dr. Stephan Mathas and Dr. Martin Janz from Professor Bernd Dörken's group at the MDC and the Charité. Their findings have now been published online in advance in Nature Immunology (doi:10.1038/ni1285, 2005)*. Their data also make it clear why it has been so difficult to find out which cells in the body are affected by the disease which was first described in the literature in 1832 by the English physician and pathologist Thomas Hodgkin. Not until 1994, 160 years after he had initially described the disease, scientists had found out that it originates in the B cells, specific white blood cells of the immune system. Now, the data of the Berlin research group also help to understand the process of normal and malignant B cell development.
The various white blood cells, as well as the red blood cells and the blood platelets, develop from blood stem cells in the bone marrow, orchestrated by different molecular switches called transcription factors. They tell the cells which direction "to go". Until now, it has been assumed that once human blood cells have developed into one direction they are no longer able to leave their path. However, experiments in mice have shown that mature B cells have the ability to do exactly this: reprogramming and developing into different cell lineages. Until now, it was unclear whether human blood cells can undergo similar processes.
Now, Dr. Mathas and Dr. Janz were able to show that in Hodgkin Reed Sternberg cells, which originate from B cells, the program which steers the differentiation of B cells is defect. One of the central regulators of B cell development, called E2A, is blocked by two antagonists, known as Id2 and ABF-1. Following inhibition of E2A, B cell characteristics are lost and genes for markers of other immune cells, such as macrophages and T cells, which are not characteristic for B cells, are upregulated. Thus, the B cells have changed their appearance. These findings shed light on the extraordinary appearance of Hodgkin Reed Sternberg lymphoma cells.
* Intrinsic inhibition of E2A by ABF-1 and Id2 mediates reprogramming of neoplastic B cells in Hodgkin lymphoma
Stephan Mathas1,2*, Martin Janz1,2*, Franziska Hummel2, Michael Hummel3, Brigitte Wollert-Wulf2, Simone Lusatis2 , Ioannis Anagnosto-poulos3, Andreas Lietz2, Mikael Sigvardsson4, Franziska Jundt1,2, Korinna Jöhrens3, Kurt Bommert2, Harald Stein3 and Bernd Dörken1,2
1Max-Delbruck-Center for Molecular Medicine, Robert-Rossle-Str. 10, 13125 Berlin; 2Hematology, Oncology and Tumorimmunology, Charite, Medical University Berlin, Campus Virchow-Klinikum, Campus Berlin-Buch, Augustenburger Platz 1, 13353 Berlin; 3Institute for Pathology, Charite, Medical University Berlin, Campus Benjamin Franklin, 12200 Berlin; 4Department for Hematopoietic Stemcell Biology, Stemcell Center, Lund University, S221 84 Lund, Sweden
*These authors contributed equally to this work
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Max Delbrück Center for Molecular Medicine(MDC) Berlin-Buch
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