Multiple myeloma (MM), also known as Kahler's disease, is a type of cancer of antibody-producing B lymphocytes (plasma cells), growing in the bone marrow (BM) and causing bone destruction. The survival and proliferation of MM cells in the BM critically depend on interaction with stromal cells. CXCL12 regulates the homing to the BM niche by mediating the transendothelial migration and adhesion/retention of the MM cells. The gamma isoform of CXCL12 (CXCL12γ) has enhanced biological activity compared to the ‘common’ CXCL12α isoform, mediated by its unique extended C-terminal domain, which binds heparan sulfate proteoglycans (HSPGs) with an extraordinary high affinity.
It was observed that CXCL12γ is expressed by stromal cells in the BM and, unlike the CXCL12α isoform, was retained on the surface of BM stromal cells (BMSCs). This membrane retention of CXCL12γ is HSPG mediated. CXCL12γ expressed by BMSCs and membrane-retained by HSPGs supported robust adhesion of multiple myeloma (MM) cells to the BMSCs and protected MM cells from bortezomib-induced cell death.
Taken together, the data suggest a scenario in which CXCL12γ functions as a ‘niche chemokine’ that, in conjunction with HSPGs, plays a key role in controlling adhesion, BM retention, and cell adhesion-mediated drug-resistance of MM cells. These findings identify this unique membrane-bound chemokine and associated HSPGs as partners in mediating MM–niche interaction and as potential therapeutic targets in MM.
Model for the role of distinct CXCL12 isoforms in the MM BM niche.
Read the full article ‘The CXCL12gamma chemokine immobilized by heparan sulfate on stromal niche cells controls adhesion and mediates drug resistance in multiple myeloma’ in the Journal of Hematology & Oncology
People involved:
All authors, except for Arenzana-Seisdedos, i.e., Zemin Ren, Hildo Lantermans, Annemieke Kuil, Willem Kraan, Marie Jose Kersten, Marcel Spaargaren*, & Steven Pals*, are affiliated with Cancer Center Amsterdam (Amsterdam UMC).
This work was supported by grants from the Dutch Cancer Society (KWF) and Lymph&Co, and by a CSC Chinese Government Scholarship.