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Blood, 15 January 2006, Vol. 107, No. 2, pp. 760-768.
Prepublished online as a Blood First Edition Paper on September 27, 2005; DOI 10.1182/blood-2005-05-1929.
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Submitted May 12, 2005
Accepted September 13, 2005
Functional analysis of HGF/MET-signaling and aberrant HGF activator expression in diffuse large B cell lymphoma
Esther P Tjin, Richard W Groen, Irma Vogelzang, Patrick W Derksen, Melanie D Klok, Helen P Meijer, Susanne van Eeden, Steven T Pals, and Marcel Spaargaren*
Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands
* Corresponding author; email: marcel.spaargaren{at}amc.uva.nl.
Inappropriate activation of MET, the receptor tyrosine kinase for hepatocyte growth factor (HGF), has been implicated in tumorigenesis. Although we have previously shown that HGF/MET signaling controls survival and proliferation of multiple myeloma (MM), its role in the pathogenesis of other B cell malignancies has remained largely unexplored. Here, we have examined a panel of 110 B cell malignancies for MET expression, which, apart from MM (48%), was found to be largely confined to diffuse large B cell lymphomas (DLBCL) (30%). No amplification of the MET gene was found, however, mutational analysis revealed two germline missense mutations: R1166Q in the tyrosine kinase domain in one patient, and R988C in the juxtamembrane domain in four patients. The R988C mutation has recently been shown to enhance tumorigenesis. In MET-positive DLBCL cells, HGF induces MEK-dependent activation of ERK and PI3K-dependent phosphorylation of PKB, GSK3 and FOXO3a. Furthermore, HGF induces PI3K-dependent  4 1 integrin-mediated adhesion to VCAM-1 and fibronectin. Within the tumor-microenvironment of DLBCL, HGF is provided by macrophages, whereas DLBCL cells themselves produce the serine protease HGF activator (HGFA), which autocatalyzes HGF activation. Taken together, these data indicate that HGF/MET-signaling, and secretion of HGFA by DLBCL cells contributes to lymphomagenesis in DLBCL.
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