Identifying intercellular signaling genes expressed in malignant plasma cells by using complementary DNA arrays

In multiple myeloma (MM), the growth of primary plasma cells depends not on ly on interieukin-6 (IL-6), but also on additional unidentified signals del ivered by the bone marrow environment. Using Atlas complementary DNA (cDNA) arrays comprising 268 genes coding for intercellular signaling molecules, this study Identified genes that are overexpressed in myeloma cells compare d to autologous B-lymphoblastoid cell lines. These genes encode the oncogen ic Tyro3 tyrosine kinase receptor, the heparin-binding epidermal growth fac tor-like growth factor (HB-EGF) that Is an epithelial autocrine tumor growt h factor, the thrombin receptor (TR) that is linked to HB-EGF and syndecan- 1 processing and to cell invasion, chemokine receptors CCR1 and CCR2, the W nt pathway actor Frizzled-related protein (FRZB), and the Notch receptor li gand Jagged 2. These data, obtained with the Atlas cDNA array, were confirm ed by reverse transcriptase-polymerase chain reaction or protein analysis o r both. Furthermore, Tyro3, HB-EGF, TR, and FRZB gene expression was docume nted in purified primary malignant plasma cells from patients with plasma c ell leukemia or MM. HB-EGF and FRZB were poorly expressed in purified polyc lonal plasma cells. Finally, HB-EGF was proved to be an essential autocrine growth factor for the XG-1 myeloma cells. This study shows the potency and the biologic relevance of cDNA arrays used to analyze simultaneously a lar ge panel of intercellular signaling genes and, by identifying several genes overexpressed in malignant plasma cells, opens new fields of investigation in MM biology. (C) 2001 by The American Society of Hematology.