Novel SLAMF1-derived peptide induces apoptosis in multiple myeloma cells by targeting IRF4 transcription factor for degradation

Abstract Multiple myeloma (MM) is the second most common hematological cancer. It remains incurable, highlighting the urgent need for novel therapeutic targets and treatment strategies. In this study, we investigated a panel of peptides derived from a functional motif of Signaling Lymphocytic Activation Molecule Family 1 (SLAMF1) with single amino acid substitutions and found that several of them exhibited potent anti-cancer activity by inducing MM cell death. The most potent peptide P7N4 significantly reduced the viability of both IL-6-dependent and -independent human myeloma cell lines (HMCLs), proteasome inhibitor-resistant MM cells, and primary MM cells, while exerting minimal effects on healthy blood cells. Furthermore, P7N4 enhanced the efficacy of the chemotherapeutic agent melphalan. When combined with the proteasome inhibitor bortezomib, P7N4 potentiated the anti-cancer effect of bortezomib in a highly aggressive murine MM model. Mechanistically, P7N4 induced apoptosis in MM cells by disrupting key pro-survival pathways, leading to reduction in IRF4, MYC, and β-catenin levels, as well as inhibition of Akt and ERK1/2 phosphorylation. Furthermore, in peptide-sensitive HMCL, P7N4 significantly altered the expression of IRF4-associated genes. These effects were likely mediated by direct interaction of peptide with IRF4, targeting this transcription factor for degradation. Overall, our findings established P7N4 as a promising therapeutic candidate for MM, warranting further optimization and in-depth mechanistic studies. Competing Interest Statement Dr. Tobias S. Slørdahl has received honoraria for the lectures from Takeda, Celgene, Amgen, Johnson&Johnson/Janssen-Cilag, Abbvie, Pfizer; for consultancy: Bristol Myers Squibb, GSK, Sanofi, Pfizer, Menarini Group; for Advisory board consultancy: Amgen, Celgene, GSK, Johnson&Johnson/Janssen-Cilag, Sanofi, Bristol Myers Squibb. None of the listed companies were contacted, or involved, or have any financial interests in the study presented in the manuscript.