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Blood, 15 May 2005, Vol. 105, No. 10, pp. 4051-4059.
Prepublished online as a Blood First Edition Paper on January 27, 2005; DOI 10.1182/blood-2004-10-4008.
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Submitted October 19, 2004
Accepted January 19, 2005
Autocrine and paracrine activated receptor tyrosine kinases in classical Hodgkin lymphoma
Christoph Renne, Klaus Willenbrock, Ralf Kuppers, Martin-Leo Hansmann, and Andreas Brauninger*
Department of Pathology, University of Frankfurt, Frankfurt, Germany; Pharmazentrum Frankfurt, Institute of Clinical Pharmacology, University of Frankfurt, Frankfurt, Germany
Department of Pathology, University of Frankfurt, Frankfurt, Germany
Institute for Cell Biology, University of Duisburg-Essen, Essen, Germany
* Corresponding author; email: braeuninger{at}em.uni-frankfurt.de.
The pathogenesis of Hodgkin lymphoma (HL) is still largely unknown. Based on a search for footprints of pathogenetic mechanisms in global RNA expression data of Hodgkin/Reed-Sternberg (HRS) cell lines, we analysed the expression and activation of six receptor tyrosine kinases (RTK) in classical HL. Immunohistochemistry revealed that the RTKs PDGFRA, DDR2, EPHB1, RON, TRKB and TRKA, were each expressed in HRS cells of 30-75% of cases. These RTKs were not expressed in normal B cells, the origin of HRS cells, nor in most B-cell non-HL. In the vast majority of cases at least one and in most cases several RTKs were coexpressed, most prominent in nodular sclerosis subtype. Phospho-tyrosine-specific antibodies revealed exemplarily activation of PDGFRA and TRKA/B and an elevated cellular phospho-tyrosine content. Immunohistochemistry for RTK ligands indicated that DDR2 and TRKA are likely activated in paracrine fashion while PDGFRA and EPHB1 seem to be activated by autocrine loops. Activating mutations were not detected in cDNAs encoding the RTKs in HRS cell lines. These findings show an unprecedented coexpression of multiple RTKs in a tumor and indicate that aberrant RTK signalling is an important factor in HL pathogenesis and a novel potential therapeutic target.
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