Bone marrow stromal cell interaction reduces Syndecan-1 expression and induces kinomic changes in myeloma cells

• Published in: Experimental cell research 2010-07, Vol.316 (11), p.1816-1828
• Main Authors: Fuhler, Gwenny M., Baanstra, Mirjam, Chesik, Daniel, Somasundaram, Rajesh, Seckinger, Anja, Hose, Dirk, Peppelenbosch, Maikel P., Bos, Nico A.
• Format: Article
• Language: English
• Subjects: Bone marrow; Bone Marrow Cells - pathology; Bone Marrow Cells - physiology; Cell Cycle; Cell Differentiation; Cell Line; Cell Line, Tumor; Cellular biology; Coculture Techniques; Drug Resistance, Neoplasm; Gene expression; Glycoproteins; Humans; Kinases; Kinome; Multiple Myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - genetics; Multiple Myeloma - pathology; Multiple Myeloma - physiopathology; Neoplastic Stem Cells - pathology; Neoplastic Stem Cells - physiology; Phosphotransferases - metabolism; Plasma; Recurrence; rho GTP-Binding Proteins - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Neoplasm - genetics; RNA, Neoplasm - metabolism; Signal Transduction; Stroma; Stromal Cells - pathology; Stromal Cells - physiology; Syndecan-1; Syndecan-1 - genetics; Syndecan-1 - metabolism; Transcription Factors - metabolism
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2010.03.013

CD138 (Syndecan 1) is a heparan sulfate proteoglycan that concentrates heparan sulfate-binding growth factors on the surface of normal and malignant plasma cells (multiple myeloma, MMC). Recent studies have shown the presence of a CD138-negative fraction of MMC within myelomatous bone marrow (BM). We employed kinome array technology to characterize this fraction at a molecular level, using a myeloma cell line model. Compared to CD138-positive cells, CD138-negative MMC showed (i) a reduced activity of kinases involved in cell cycle progression, in agreement with a decreased labeling index and (ii) reduced Rho signaling to F-actin. Interestingly, CD138 mRNA and protein expression was reduced upon interaction of MM cells with stromal cell lines and primary mesenchymal cultures, which was accompanied by the acquisition of an increased Bcl6/Blimp1 ratio. Co-culture induced an increased activity of kinases involved in adhesion and a decreased S-phase transition in both CD138-positive and -negative fractions. In addition, CD138-negative MMC demonstrated an increased STAT3 and ERK1/2 activation compared to CD138+ MMC, in agreement with a lower sensitivity to compound exposure. The presence of a less mature, more resistant CD138-negative myeloma cell fraction within bone marrow microniches might contribute to high incidence of relapse of Myeloma patients.