Junctional Adhesion Molecule-A (JAM-A) Associates With High-Risk Disease in Multiple Myeloma Patients and a...

Multiple myeloma (MM) is an incurable malignancy of terminally-differentiated plasma cells that represents a major clinical challenge despite unprecedented therapeutic advances, particularly for patients with cytogenetically-defined high-risk MM (HR-MM). Updated in 2025, the evolving cytogenetic classification of HR-MM includes gains or amplifications in chromosome 1q. One gene of emerging interest on chromosome 1q is F11R, which codes for a protein called Junctional Adhesion Molecule-A (JAM-A). Upregulation of JAM-A has been linked with the development of several aggressive malignancies, most recently MM. In the current study, F11R gene expression was found to be significantly higher in gain/amp(1q) MM patients from the CoMMpass database, and to correlate with poorer overall survival in MM patients. Furthermore, elevated F11R expression was accompanied by an increased burden of circulating CD138⁺ cells, potentially an early hallmark of extramedullary disease (EMD). As JAM-A signalling putatively promotes tumorigenic behaviour through cis-dimerization-dependent adhesion signalling, structure-based rational design principles were utilised to design novel peptide inhibitors that selectively disrupt JAM-A cis-dimerization. In vitro testing of novel peptides across a panel of MM cell lines and primary CD138+ cells from MM patients demonstrated anti-proliferative and pro-senescence properties of the novel peptides. Moreover, candidate peptide P4 significantly inhibited the growth of CD138+ plasmacytoma-like tumours in an in vivo xenograft model involving implantation onto the chick chorioallantoic membrane. Collectively, these findings support the validity of JAM-A as an emerging druggable target and provide a strong rationale for further preclinical investigations of JAM-A inhibitors in MM.