Immunoglobulin Free Light Chains and GAGs Mediate Multiple Myeloma Extracellular Vesicles Uptake and Secondary NfκB...

Area of Science:

• Hematology
• Cell Biology
• Biochemistry

Background:

• Multiple myeloma (MM) is a plasma cell malignancy characterized by abnormal cell persistence in bone marrow.
• Secreted immunoglobulin free light chains (FLCs) from monoclonal plasma cells can cause tissue damage.
• Extracellular vesicles (EVs) derived from MM serum exhibit distinct phenotypes compared to those from monoclonal gammopathy of undetermined significance (MGUS).

Purpose of the Study:

• To investigate the biological activity of MM and MGUS serum-derived EVs on endothelial and myocardial cells.
• To identify specific molecular targets involved in MM EV uptake and processing.
• To explore the role of FLCs and glycosaminoglycans in MM EV-mediated cellular effects.

Main Methods:

• Differential ultracentrifugation was used to purify EVs from MM and MGUS patient sera.
• Endothelial and myocardial cell lines were exposed to purified EVs to assess proliferation and internalization.
• EVs were pre-treated with anti-FLCs antibodies or heparin to block uptake and analyze downstream signaling.
• Nuclear factor kappa B (NF-κB) translocation and c-src kinase activity were measured.

Main Results:

• MM and MGUS EVs demonstrated differential effects on endothelial and myocardial cell proliferation and internalization.
• Pre-treatment of MM EVs with anti-FLCs antibodies or heparin significantly inhibited their uptake by cells.
• MM EV exposure induced nuclear translocation of NF-κB, which was blocked by anti-FLCs antibodies and heparin.
• The protein tyrosine kinase c-src was found on MM EVs and redistributed upon cell exposure, an effect also blocked by pre-treatment.

Conclusions:

• FLCs and glycosaminoglycans are key mediators of MM EV uptake and subsequent cellular responses, including NF-κB activation and c-src kinase redistribution.
• Circulating MM EVs possess distinct biological activities influencing target cells, potentially contributing to MM pathogenesis.
• These findings suggest novel therapeutic targets and diagnostic biomarkers for MM based on EV-FLC interactions.