The Role of AP-1 Transcription Factors in Plasma Cell Biology and Multiple Myeloma Pathophysiology

SIMPLE SUMMARY: As convergence points of signaling cascades, transcription factors (TFs) play a crucial role in cell physiology, including B cell differentiation, and are deregulated in solid and hematologic malignancies, including multiple myeloma (MM), a malignant clonal plasma cell proliferative disorder. In particular, there is accumulating evidence that aberrant gene expression programs induced by the Activator Protein-1 (AP-1) TF family are associated with MM cell growth, survival, migration, drug resistance, bone marrow angiogenesis and bone disease. Therefore AP-1 TFs, which have been deemed as “undruggable” until most recently, represent appealing targets for novel therapeutic approaches. Indeed, strategies to target TFs such as AP-1 emerge among today’s most promising anti-MM therapies. ABSTRACT: Multiple myeloma (MM) is an incurable hematologic malignancy characterized by the clonal expansion of malignant plasma cells within the bone marrow. Activator Protein-1 (AP-1) transcription factors (TFs), comprised of the JUN, FOS, ATF and MAF multigene families, are implicated in a plethora of physiologic processes and tumorigenesis including plasma cell differentiation and MM pathogenesis. Depending on the genetic background, the tumor stage, and cues of the tumor microenvironment, specific dimeric AP-1 complexes are formed. For example, AP-1 complexes containing Fra-1, Fra-2 and B-ATF play central roles in the transcriptional control of B cell development and plasma cell differentiation, while dysregulation of AP-1 family members c-Maf, c-Jun, and JunB is associated with MM cell proliferation, survival, drug resistance, bone marrow angiogenesis, and bone disease. The present review article summarizes our up-to-date knowledge on the role of AP-1 family members in plasma cell differentiation and MM pathophysiology. Moreover, it discusses novel, rationally derived approaches to therapeutically target AP-1 TFs, including protein-protein and protein-DNA binding inhibitors, epigenetic modifiers and natural products.