“Junk DNA” drives cancer growth
“We have shown this is the case in Hodgkin’s lymphoma, but the exact same mechanism could be involved in the development of other forms of blood cancer,” said Prof. Bonifer. “This would have implications for diagnosis, prognosis, and therapy of these diseases.”
‘Long terminal repeats’ (LTRs) are a form of ‘junk DNA’ - genetic material that has accumulated in the human genome over millions of years. Although LTRs originate from viruses and are potentially harmful, they are usually made inactive when embryos are developing in the womb.
If this process of inactivation doesn’t work, then the LTRs could activate cancer genes, a possibility that was suggested in previous animal studies. This latest research has now demonstrated for the first time that these ‘rogue’ active LTRs can drive the growth of cancer in humans.
The work focused on cancerous cells of Hodgkin’s lymphoma (the Hodgkin-/Reed Sternberg cells) that originate from white blood cells (antibody-producing B cells). Unusually, this type of lymphoma cell does not contain a so-called ‘growth factor receptor’ that normally controls the growth of other B-cells.
They found that the lymphoma cells’ growth was dependent on a receptor that normally regulates the growth of other immune cells, but it is not usually found in B-cells. However in this case, the Hodgkin-/Reed Sternberg cells ‘hijacked’ this receptor (CSF1R, the colony stimulating factor 1 receptor) for their own purposes by activating some of the ‘junk DNA’. In fact the lymphoma cells activated hundreds, if not thousands, of LTRs all over the genome, not just one.
Hodgkin-/Reed Sternberg cells may not be the only cells that use this method to subvert normal controls of cell growth. The researchers found evidence of the same LTRs activating the same growth receptor in anaplastic large cell lymphoma, another blood cancer.
The consequences of such widespread LTR activation are currently still unclear, according to the study’s authors. Such processes could potentially activate other genes involved in tumour development. It could also affect the stability of chromosomes of lymphoma cells, a factor that may explain why Hodgkin-/Reed Sternberg cells gain many chromosomal abnormalities over time and become more and more malignant.
Björn Lamprecht1,2,10, Korden Walter3,10, Stephan Kreher1,2,10, Raman Kumar4, Michael Hummel5, Dido Lenze5, Karl Köchert1,2, Mohamed Amine Bouhlel3, Julia Richter6, Eric Soler7, Ralph Stadhouders7, Korinna Jöhrens5, Kathrin D. Wurster1,2, David Callen4, Michael F. Harte8, Maciej Giefing6,9, Rachael Barlow3, Harald Stein5, Ioannis Anagnostopoulos5, Martin Janz1,2, Peter N. Cockerill3, Reiner Siebert6, Bernd Dörken1,2, Constanze Bonifer3, and Stephan Mathas1,2
1Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany; 2Hematology, Oncology and Tumorimmunology, Charité University Medical School, CVK, 13353 Berlin, Germany; 3Section of Experimental Haematology, Leeds Institute of Molecular Medicine, University of Leeds, St. James's University Hospital, Leeds LS9 7TF, UK; 4Breast Cancer Genetics Group, Discipline of Medicine, University of Adelaide and Hanson Institute, Adelaide, South Australia 5000, Australia; 5Institute of Pathology, Charité University Medical School, CBF, 12200 Berlin, Germany; 6Institute of Human Genetics, Christian-Albrechts University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; 7Erasmus MC, University Medical Center, Department of Cell Biology, 3015 GE Rotterdam; 8Cytopia Research Pty Ltd, Richmond, Victoria 3121, Australia; 9Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland. 10These authors contributed equally to this work
Dr. Stephan Mathas
Max-Delbrück-Center for Molecular Medicine and Charité University Medical School
Tel.: 49 30 9406 2863, Fax: 49 30 94063124
email: stephan.mathas@charite.de
Professor Constanze Bonifer
University of Leeds
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email c.bonifer@leeds.ac.uk
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