Multiple myeloma: A tale of deregulated transcription factors

A comprehensive understanding of the molecular mechanisms underlying multiple myeloma (MM) pathogenesis is essential for developing therapeutic strategies that overcome disease heterogeneity and treatment relapse. In this review, we focus on transcription factors (TFs), key regulators of gene expression that play critical roles in normal hematopoiesis and MM biology. We first discuss the physiological functions of TFs in lymphoid lineage commitment and terminal B-cell differentiation into plasma cells. This provides insights into the contribution of key TFs, such as IRF4 and PRDM1, to development of MM. We then examine the regulatory mechanisms of TFs in MM, exploring how their deregulation participates in the pathogenesis of the disease. We summarize the roles of major TF families, highlighting both well-established TFs essential for MM pathogenesis and emerging TFs with potential clinical relevance. In addition to their functional roles, several TFs show promise as biomarkers for patient stratification and risk assessment. Finally, we discuss recent advances that challenge the notion of TFs as "undruggable", including siRNA-loaded lipid nanoparticles or Proteolysis-Targeting Chimeras (PROTACs), which offer novel opportunities to therapeutically modulate TF activity. These strategies could enable the development of novel interventions aimed at improving clinical outcomes and quality of life for MM patients. Collectively, this review integrates physiological and pathological insights into TF function in MM and underscores their potential as biomarkers and actionable targets in precision medicine.