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What Sets the Stone Rolling - New Insights into Cancer Pathogenesis

Dr. Stephan Mathas and Professor Bernd Dörken of the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch and Charité – Medical University Berlin, in close cooperation with Professor Tom Misteli of the National Cancer Institute, Bethesda, MD, USA, have identified three cancer genes involved in the pathogenesis of a cancer of the lymphatic system.

At the same time they were able to shed light on the translocation process, which also plays a crucial role in cancer pathogenesis. During translocation, fragments of genes move from one chromosome to another and fuse – if they are close enough to each other – to a new gene. This fusion gene additionally stimulates the growth of cancer genes. (PNAS, Early Edition, 2009, doi:10.1073/pnas.0900912106).

Researchers and clinicians found clues to this process while studying anaplastic large cell lymphoma (ALCL), a disease of the lymphatic system, which belongs to the group of non-Hodgkin’s lymphomas. In this disease specific blood cells of the immune system, the T cells, are affected: within the nuclear space of the T cell, gene fragments can move from chromosome 2 to chromosome 5, thereby forming a fusion gene (NPM-ALK). Such fusion genes can trigger uncontrolled growth of cells. However, in 40 percent of patients with ALCL, no translocation can be detected in the blood cells. What triggers the disease is still unknown.

As Dr. Mathas explained, in ALCL cells the three genes they identified are falsely “massively up-regulated”. “Normally, these genes are never active in a T cell,” Dr. Mathas said. “In ALCL, however, they play a fundamental role.” The three identified genes, which have the scientific abbreviations Fra2, Id2 and CSF1 receptor, can function as oncogenes which cause cells to grow in an uncontrolled and uninhibited manner. The first two genes are on chromosome 2, the last-mentioned gene on chromosome 5 – all of them near the chromosome breakpoints which lead to ALCL-typical translocation. Moreover, Fra2 and Id2 are amplified in ALCL, which means that several copies of these genes are present in the cell, additionally stimulating cancer pathogenesis.

Aberrant up-regulation facilitates the occurrence of translocations

Furthermore, the researchers were able to show that aberrant up-regulation of these genes leads to a close proximity of the chromosome fragments 2 and 5 within the cellular nuclear space. Typically these fragments fuse with each other in ALCL cells. The researchers were also able to reproduce this fusion process experimentally. They conclude that the aberrant activity of these three cancer genes is one of the prerequisites for ALCL pathogenesis and precedes the formation of the translocation. Moreover, these data for the first time directly support the hypothesis that translocations only can occur when the chromosomes in question are spatially close together prior to translocation.

*Gene deregulation and spatial genome reorganization near breakpoints
prior to formation of translocations in ALCL

Stephan Mathas*†, Stephan Kreher*†, Karen J.
Meaburn, Korinna Jöhrens§, Björn Lamprecht*†,
Chalid Assaf, Wolfram Sterry, Marshall E. Kadin||,
Masanori Daibata**, Stefan Joos††, Michael Hummel§,
Harald Stein§, Martin Janz*†, Ioannis Anagnostopoulos§,
Evelin Schrock‡‡, Tom Misteli, and Bernd Dörken*†

for Molecular Medicine, Robert-Rössle-Str. 10, 13125 Berlin, Germany; Hematology,
Oncology and Tumorimmunology, Charité, Medical University Berlin, CVK,
Augustenburger Platz 1, 13353 Berlin, Germany; Cell Biology of
Genomes, National Cancer Institute, NIH, Bethesda, 41 Library Drive, MD 20892,
USA; §Institute of Pathology, Charité, Medical University Berlin,
CBF, Hindenburgdamm 30, 12200 Berlin, Germany;Department of
Dermatology, Allergy and Venerology, Skin Cancer Center Charité, Medical
University Berlin, Charitéplatz 1, 10117 Berlin, Germany; ||Department
of Pathology, Harvard Medical School, Boston, MA 02115, USA and Department of
Dermatology and Skin Surgery, Roger Williams Medical Center, 50 Maude Street,
Providence, RI 02908, USA; **Department of Hematology, Kochi Medical
School, Kohasu, Okoh-cho, Nankuko-city, Kochi 783-8505, Japan; ††German
Cancer Research Center, B060, Im Neuenheimer Feld 280, 69120 Heidelberg,
Germany; ‡‡Institute for Clinical Genetics, Dresden University of
Technology, Fetscherstr. 74, 01307 Dresden,

Barbara Bachtler
Press and Public Affairs
Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch
Robert-Rössle-Strasse 10; 13125 Berlin; Germany
Phone: +49 (0) 30 94 06 - 38 96
Fax:     +49 (0) 30 94 06 - 38 33

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