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APRIL and TACI interact with syndecan-1 on the surface of multiple myeloma cells to form an essential survival loop
Jérôme Moreaux1, Anne-Catherine Sprynski, Stacey R Dillon
1CHU Montpellier, Institute of Research in Biotherapy, Montpellier, France.
Abstract:
BLyS and APRIL share two receptors - transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B-cell maturation antigen (BCMA) - and BLyS binds to a third receptor, BAFF-R. We previously reported that TACI gene expression is a good indicator of a BLyS-binding receptor in human multiple myeloma cell lines (HMCLs), unlike BCMA, which is expressed by all HMCLs or BAFF-R which is typically not expressed by late-stage B cells. We hypothesised a link between APRIL and TACI through syndecan-1, similar to the situation reported for FGF and FGFR. We observed very strong binding of APRIL, but not BLyS, at the surface of all syndecan-1(+) HMCLs and primary multiple myeloma cells (MMC). All syndecan-1(+) HMCLs and MMC could also bind TACI-Fc, but not BCMA-Fc or BAFF-R-Fc molecules. Binding of APRIL or TACI-Fc was abrogated by heparin or cell pretreatment with heparitinase, which cleaves heparan sulfate chains. The growth factor activity of APRIL on MMC was also inhibited by heparin. Our data identify syndecan-1 as a co-receptor for APRIL and TACI at the cell surface of MMC, promoting the activation of an APRIL/TACI pathway that induces survival and proliferation in MMC.
Insights
Syndecan-1 acts as a co-receptor for APRIL and TACI in multiple myeloma cells. This interaction activates a pathway promoting cancer cell survival and proliferation.
Area of Science:
- Hematology
- Molecular Biology
- Cell Biology
Background:
- B-cell activating factor (BAFF) and A PRoliferation-Inducing Ligand (APRIL) are key cytokines in B-cell biology.
- Transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), B-cell maturation antigen (BCMA), and BAFF receptor (BAFF-R) are receptors for BAFF and APRIL.
- Syndecan-1 is a cell surface proteoglycan implicated in various cellular processes.
Purpose of the Study:
- To investigate the role of syndecan-1 as a co-receptor for APRIL and TACI in human multiple myeloma cell lines (HMCLs) and primary multiple myeloma cells (MMC).
- To elucidate the mechanism by which APRIL and TACI interact with syndecan-1 to influence myeloma cell growth.
Main Methods:
- Binding assays using APRIL, TACI-Fc, BCMA-Fc, and BAFF-R-Fc on syndecan-1 positive (syndecan-1(+)) HMCLs and MMC.
- Inhibition studies using heparin and heparitinase to assess the role of heparan sulfate chains.
- Assessment of APRIL's growth factor activity on MMC.
Main Results:
- APRIL, but not BAFF, strongly bound to the surface of syndecan-1(+) HMCLs and MMC.
- Syndecan-1(+) HMCLs and MMC bound TACI-Fc, but not BCMA-Fc or BAFF-R-Fc.
- Binding of APRIL and TACI-Fc was blocked by heparin and heparitinase, indicating the involvement of heparan sulfate chains.
- Heparin inhibited APRIL's growth-promoting activity on MMC.
Conclusions:
- Syndecan-1 functions as a co-receptor for APRIL and TACI on the surface of multiple myeloma cells.
- The APRIL/TACI pathway, mediated by syndecan-1, promotes the survival and proliferation of multiple myeloma cells.
- Targeting the syndecan-1/APRIL/TACI axis may offer a therapeutic strategy for multiple myeloma.
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