Fig. 7

BMSC-derived CXCL12γ immobilized by HSPGs mediates CAM-DR. a Transwells co-culture of MM cells with BMSCs. XG1 and MM1.S cells were cultured either alone in the upper compartment or co-cultured with HS5-WT, HS5-CXCL12γKO, or HS5-EXT1KO in the lower compartment of the transwells, in the presence of bortezomib for 3 days. So, the transwells physically separate the MM cells from the HS5 BMSCs. The viability of the MM cells was analyzed by flow cytometry. Mean ± SD of three independent experiments in triplicate. *P ≤ 0.05 using one-way ANOVA; b CXCL12γ-controlled drug resistance requires direct cell–cell contact between MM cells and BMSCs. MM cells were cultured, either alone or co-cultured with HS5-WT, HS5-CXCL12γKO, or HS5-EXT1KO, in the presence of bortezomib for 3 days. The MM cells in suspension were removed. The viability of the remaining MM cells was analyzed by flow cytometry. Mean ± SD of three independent experiments in triplicate is shown. ***P ≤ 0.001 using one-way ANOVA. c Model for the role of distinct CXCL12 isoforms in the MM BM niche. Specialized CAR-like BMSCs in the niche secrete high levels of CXCL12, including CXCL12α and CXCL12γ. CXCL12α shows a relatively low affinity to HSPG and, upon secretion by BMSCs, will create a chemo-attractive gradient attracting MM cells to the niche. By contrast, CXCL12γ, having an extremely high affinity for HSPG, will be immobilized by HSPGs on the cell surface of BMSCs, inducing MM adhesion to the BMSCs. This CXCL12γ-controlled adhesion serves to retain MM cells in close physical contact with the BMSCs, providing MM cells with growth and survival signals through integrin receptors as well as with access to short-range growth and survival factors. This HSPG-immobilized CXCL12γ plays an important role in MM cell retention in the BM niche as well as in cell adhesion-mediated drug (CAM-DR) resistance in MM