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Disappearance of Genetic Material Allows Tumor Cells to Grow

Loss of a gene regulator is crucial for a rare type of skin cancer - Scientists at the Max Delbrück Centrum für Molekulare Medizin (MDC) Berlin-Buch, Charité – Universitätsmedizin Berlin, the Max-Planck-Institut für Molekulare Genetik Berlin, and four other German institutes have succeeded in proving a specific gene loss in a certain human lymphoma, the genesis of which is largely unexplained to date.

The researchers investigated the Sézary syndrome, 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(Vol. 208, No. 8, 1585-1593; doi/10.1084/jem.20101785)*, 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. In contrast to 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 an essential role in this context because the gene is normally of great importance for natural lymphocyte development," explains explained 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 so far remained elusive.

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," emphasized Stephan Mathas, a scientist at the Charité Klinik für Hämatologie und Onkologie and at MDC. Consequently, it was directly proven for the first time that E2A in humans has the function of a tumor suppressor.

The researchers hope that these findings will lead to the development of new, more effective treatment concepts for patients with Sézary syndrome.

* Genomic loss of the putative tumor suppressor gene E2A in human lymphoma

Anne Steininger,1 Markus Möbs,2 Reinhard Ullmann,1 Karl Köchert,4 Stephan Kreher,4 Björn Lamprecht,4 Ioannis Anagnostopoulos,3 Michael Hummel,3 Julia Richter,5 Marc Beyer,2 Martin Janz,4 Claus-Detlev Klemke,6 Harald Stein,3 Bernd Dörken,4 Wolfram Sterry,2 Evelin Schrock,7 Stephan Mathas,4 and Chalid Assaf2,8

1Max Planck Institute for
Molecular Genetics, 14195 Berlin, Germany, 2Department of
Dermatology and Allergy, Skin Cancer Center Charité, 3Institute of
Pathology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany, 4Hematology,
Oncology and Tumorimmunology, Charité-Universitätsmedizin Berlin and
Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany, 5Institute
of Human Genetics, Christian-Albrechts-University Kiel and University Hospital
Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany, 6Department of
Dermatology, University Medical Center Mannheim, Ruprecht-Karls-University of
Heidelberg, 68167 Mannheim, Germany, 7Institute for Clinical
Genetics, Dresden University of Technology, 01307 Dresden, Germany, 8HELIOS
Klinikum Krefeld, 47805 Krefeld, Germany

Barbara Bachtler
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