1. ¹INSERM, U475, Montpellier, France
2. ²CHU Montpellier, Institute of Research in Biotherapy, France
3. ³Medizinische Klinik und Poliklinik V, Universitätsklinikum Heidelberg, INF410, Heidelberg, Germany
4. ⁴Clinical Hematology Department, CHU Montpellier, France

Correspondence: Dr B Klein, INSERM U475, 99 Rue Puech Villa, 34197 Montpellier, France. E-mail: klein@montp.inserm.fr

Received 23 December 2005; Revised 13 April 2006; Accepted 19 April 2006; Published online 29 May 2006.

Abstract

The epidermal growth factor (EGF)/EGF-receptor (ErbB1-4) family is involved in the biology of multiple myeloma (MM). In particular, ErbB-specific inhibitors induce strong apoptosis of myeloma cells (MMC) in vitro. To delineate the contribution of the 10 EGF-family ligands to the pathogenesis of MM, we have assessed their expression and biological activity. Comparing Affymetrix DNA-microarray-expression-profiles of CD138-purified plasma-cells from 65 MM-patients and 7 normal individuals to those of plasmablasts and B-cells, we found 5/10 EGF-family genes to be expressed in MMC. Neuregulin-2 and neuregulin-3 were expressed by MMC only, while neuregulin-1, amphiregulin and transforming growth factor- were expressed by both MMC and normal plasma-cells. Using real-time polymerase chain reaction, we found HB-EGF, amphiregulin, neuregulin-1 and epiregulin to be expressed by cells from the bone marrow-environment. Only the EGF-members able to bind heparan-sulphate proteoglycans (HSPGs) – neuregulin-1, amphiregulin, HB-EGF – promote the growth of MMC. Those ligands strongly bind MMC through HSPGs. The binding and the MMC growth activity was abrogated by heparitinase, heparin or deletion of the HS-binding domain. The number of HS-binding EGF ligand molecules bound to MMC was higher than 10⁵ molecules/cell and paralleled that of syndecan-1. Syndecan-1, the main HSPG present on MM cells, likely concentrates high levels of HS-binding-EGF-ligands at the cell membrane and facilitates ErbB-activation. Altogether, our data further identify EGF-signalling as promising target for MM-therapy.