CD86 regulates a pro-survival signal in myeloma cells

While multiple myeloma patient prognosis has improved over the past decade, research towards discovery of new therapeutic avenues is important, and could lead to a cure for this chronic plasma cell malignancy. Data analysis from a myeloma patient database shows that the CD28-CD86 signaling module may provide a survival advantage in myeloma cells that negatively impacts patient outcome. Here we show that blocking the CD28-CD86 pathway, by silencing or with CTLA-4-Ig, leads to myeloma cell death. Blockade of this pathway leads to downregulation of nutrient transporters, integrins, and IRF4, a known myeloma survival factor. Our data also indicate that CD86, the canonical "ligand" in this pathway, is mediating a pro-survival signal via the cytosolic domain that has not been previously described. These findings indicate that blockade of this pathway is a promising therapeutic avenue for myeloma, as it leads to modulation of different processes important in cell viability. The myeloma cell lines MM.1s, RPMI8226, KMS18, and RPMI8226 that overexpresses the anti-apoptotic protein Mcl1 were transfected with short hairpin RNAs targeting CD28, CD86, Gapdh (control), or empty vector (pLK0.1) control and gene expression analysis was performed by RNA-seq.