Redefining CD56 as a biomarker and therapeutic target in Multiple Myeloma

Multiple myeloma (MM) cells aberrantly express surface antigens compared to normal plasma cells. Among others, CD56 is present at variable levels in approximately 70% of MM patients; however very little is known about CD56 role in MM. We demonstrated that MM patients with more than 10 percent of CD56-expressing clonal MM cells have inferior clinical outcomes. By gain-of and loss-of function models, we revealed that CD56 promotes MM cell growth, survival, and adhesion to stromal cells. These protumoral effects are induced by the activation of the RSK2/CREB1 signaling pathway, with increased mRNA and protein levels of the anti-apoptotic genes BCL2 and MCL1. Consequently, the genomic and pharmacological inhibition of RSK2 or CREB1 specifically induced MM cell death in CD56-expressing MM cells. Finally, we observed that CD56 signaling decreases CRBN expression, reducing responses to lenalidomide. RSK2 or CREB1 inhibition increased CRBN levels and were synergic with lenalidomide in inducing cell death, especially in CD56-expressing MM cells. In conclusion, our findings demonstrate that CD56 promotes MM cell growth, and pave the way to novel therapies based on targeting CD56, along with the use of CD56 as a predictive biomarker for MM therapies. Implications: Multiple myeloma (MM) is an incurable, genetically heterogeneous disease, without available tailored therapeutic approaches. CD56 signaling promotes MM growth and adhesion, by activating CREB1 target genes, MCL1 and BCL2. Inhibition of CREB1 alone or in combination with lenalidomide is an unexplored synthetic lethal approach in CD56-expressing MM patients.