Multiple myeloma (MM) is a malignancy of plasma cells (PC) that grow within the bone marrow and maintain massive immunoglobulin (Ig) production. Disease evolution is driven by genetic lesions, whose effects on cell biology and fitness underlie addictions and vulnerabilities of myeloma cells. Several genes mutated in myeloma are strictly involved in dictating PC identity and antibody factory function. Here, we evaluate the impact of mutations in IRF4, PRDM1, and XBP1, essential transcription factors driving the B to PC differentiation, on MM cell biology and homeostasis. These factors are highly specialized, with limited overlap in their downstream transcriptional programs. Indeed, IRF4 sustains metabolism, survival, and proliferation, while PRDM1 and XBP1 are mainly responsible for endoplasmic reticulum expansion and sustained Ig secretion. Interestingly, IRF4 undergoes activating mutations and translocations, while PRDM1 and XBP1 are hit by loss-of-function events, raising the hypothesis that containment of the secretory program, but not its complete extinction, may be beneficial to malignant PCs. Finally, recent studies unveiled that also the PRDM1 target, FAM46C/TENT5C, an onco-suppressor uniquely and frequently mutated or deleted in myeloma, is directly and potently involved in orchestrating ER homeostasis and secretory activity. Inactivating mutations found in this gene and its interactors strengthen the notion that reduced secretory capacity confers advantage to myeloma cells. We believe that dissection of the evolutionary pressure on genes driving PC-specific functions in myeloma will disclose the cellular strategies by which myeloma cells maintain an equilibrium between antibody production and survival, thus unveiling novel therapeutic targets.
