Aug 3 2011
Scientists at Charité - Universitätsmedizin Berlin, Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch, the Max-Planck-Institut für Molekulare Genetik Berlin, and four other German institutes succeeded in proving a specific gene loss in a certain human lymphoma, the genesis of which is largely unexplained to date. They investigated the so-called Sézary syndrome. This is an aggressive cancer disease from the group of primary skin lymphomas, the so-called "primary cutaneous lymphomas." The results of the study, which were published in the current issue of the Journal of Experimental Medicine, provide fundamentally new insights into the genesis and development of Sézary syndrome and possibly other human lymphomas as well.
Malignant Sézary syndrome is characterized by the reproduction of a special type of white blood cells in the skin of male and female patients. By contrast with most other skin lymphomas, patients with Sézary syndrome manifest not only skin contamination but also contamination of blood and lymph nodes by degenerate T cells even at the onset of the disease. The researchers investigated highly purified tumor cells from patients with Sézary syndrome using modern, high-resolution genetic procedures (the so-called array comparative genomic hybridization technique) for hitherto unknown genetic changes. In doing so they identified areas in the genotype of these tumor cells that have become lost in many of the patients examined. A detailed analysis of these areas showed that one of the most frequently affected genes codes for a so-called transcription factor. Transcription factors have key functions in the regulation of cellular gene activity.
"The partial loss of the gene for transcription factor E2A appears to play a very key role in this context because the gene is normally of great importance for natural lymphocyte development," explains Chalid Assaf from the Charité Klinik für Dermatologie, Venerologie und Allergologie. In mice a loss of this gene leads to the genesis of aggressive T cell lymphomas. However, a gene loss in one of the various human lymphoma classes had not yet been found so far.
The researchers also identified several E2A-regulated genes and signal paths in tumor cells, the mere deregulation of each of which is sufficient to enable a tumor to develop. "Loss of E2A in Sézary syndrome is of crucial importance for the aggressive behavior of tumor cells because it contributes to more rapid, uncontrolled growth of cells," emphasizes Stephan Mathas, a scientist at the Charité Klinik für Hämatologie und Onkologie and at MDC. Consequently, it was directly proved for the first time that E2A in humans has the function of a tumor suppressor. The researchers hope that these findings might in future possibly represent the basis for the development of new treatment concepts to offer patients with Sézary syndrome new and more effective therapies.
Max Delbrück Center for Molecular Medicine