C-src enriched serum microvesicles are generated in malignant plasma cell dyscrasia.
Plasma cell dyscrasias are immunosecretory disorders that can lead to hematological malignancies such as Multiple Myeloma (MM). MM accounts for 15% of all hematologic cancers, and those diagnosed with MM typically become severely ill and have a low life expectancy. Monoclonal immunoglobulin Free Light Chains (FLC) are present in the serum and urine of many patients with plasma cell diseases. The biological differences between monoclonal FLCs, produced under malignant or benign dyscrasias, has not yet been characterized. In the present study, we show that endothelial and heart muscle cell lines internalize kappa and lambda FLCs. After internalization, FLCs are rerouted in the extracellular space via microvesicles and exosomes that can be re-internalized in contiguous cells. Only FLCs secreted from malignant B Lymphocytes were carried in Hsp70, annexin V, and c-src positive vesicles. In both MM and AL Amyloidosis patients we observed an increase in microvesicle and exosome production. Isolated serum vesicles from MM, AL Amyloidosis and monoclonal gammopathy of undetermined significance (MGUS) patients contained FLCs. Furthermore MM and AL amyloidosis vesicles were strongly positive for Hsp70, annexin V, and c-src compared to MGUS and control patients. These are the first data implying that FLCs reroute via microvesicles in the blood stream, and also suggest a potential novel mechanism of c-src activation in plasma cell dyscrasia.
Department of Molecular and Translational Medicine, Faculty of Medicine, University of Brescia, Brescia, Italy.
Giuseppe
G
Di Noto
Lucia
L
Paolini
Andrea
A
Zendrini
Annalisa
A
Radeghieri
Luigi
L
Caimi
Doris
D
Ricotta
D017304:Annexin A5 / Q000378:metabolism; D000081247:CSK Tyrosine-Protein Kinase; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000473:pathology; D004789:Enzyme Activation; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000378:metabolism; D010265:Paraproteinemias / Q000097:blood / Q000201:enzymology*; D021381:Protein Transport; D022142:Secretory Vesicles / Q000201:enzymology*; D019061:src-Family Kinases / Q000378:metabolism*
D017304:Annexin A5; D018840:HSP70 Heat-Shock Proteins; D007147:Immunoglobulin Light Chains; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human