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Blood, 1 June 2007, Vol. 109, No. 11, pp. 4914-4923.
Prepublished online as a Blood First Edition Paper on March 5, 2007; DOI 10.1182/blood-2006-08-043232.
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Submitted August 23, 2006
Accepted February 8, 2007
Heparanase influences expression and shedding of syndecan-1, and its expression by the bone marrow environment is a bad prognostic factor in multiple myeloma
Karene Mahtouk, Dirk Hose, Pierre Raynaud, Michael Hundemer, Michel Jourdan, Eric Jourdan, Veronique Pantesco, Marion Baudard, John De Vos, Marion Larroque, Thomas Moehler, Jean-Francois Rossi, Thierry Reme, Hartmut Goldschmidt, and Bernard Klein*
Institute of Research in Biotherapy, CHU Montpellier, Montpellier, France
Medizinische Klinik und Poliklinik V, Universitatsklinikum Heidelberg, Heidelberg, Germany
INSERM U847, Montpellier, France
Department of Hematology and Clinical Oncology, CHU Montpellier, Montpellier, France
Universite Montpellier, Montpellier, France
Nationales Centrum fur Tumorerkrankungen, Heidelberg, Germany
* Corresponding author; email: klein{at}montp.inserm.fr.
The heparan sulfate (HS) proteoglycan, syndecan-1, plays a major role in multiple myeloma (MM) by concentrating heparin-binding growth factors on the surface of MM cells (MMC). Using Affymetrix microarrays and real-time RT-PCR, we show that the gene encoding heparanase (HPSE), an enzyme that cleaves HS-chains, is expressed by 11/19 myeloma cell lines (HMCLs). In HSPE-positive HMCLs, syndecan-1 gene expression and production of soluble syndecan-1, unlike expression of membrane syndecan-1, were significantly increased. Knockdown of HPSE by siRNA resulted in a decrease of syndecan-1 expression and soluble syndecan-1 production without affecting membrane syndecan-1 expression. Thus, HPSE influences expression and shedding of syndecan-1. Contrary to HMCLs, HPSE is expressed in only 4/39 primary MMC samples, whereas it is expressed in 36/39 bone marrow (BM) microenvironment samples. In the latter, HPSE is expressed at a median level in polymorphonuclear cells and T cells; it is highly expressed in monocytes and osteoclasts. Affymetrix data were validated at the protein level, both on HMCLs and patient samples. We report for the first time that a gene's expression mainly in the BM environment, i.e. HSPE, is associated with a shorter event-free survival of newly diagnosed myeloma patients treated with high-dose chemotherapy and stem cell transplantation. Our study suggests that clinical inhibitors of HPSE could be beneficial for patients with MM.
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