The differentiation and stress response factor XBP-1 drives multiple myeloma pathogenesis

Multiple myeloma. (MM) evolves from a highly prevalent premalignant condition termed MGUS. The factors underlying the malignant transformation of MGUS are unknown. We report a MGUS/MM phenotype in transgenic mice with E mu-directed expression of the XBP-1 spliced isoform (XBP-1 s), a factor governing unfolded protein/ER stress response and plasma-cell development. E mu-XPB-1s elicited elevated serum Ig and skin alterations. With age, E mu-xbp-ls transgenics develop features diagnostic of human MM, including bone lytic lesions and subendothelial Ig deposition. Furthermore, transcriptional profiles of E mu-xbp-1s lymphoid and MM cells show aberrant expression of known human MM dysregulated genes. The similarities of this model with the human disease, coupled with documented frequent XBP-1 s overexpression in human MM, serve to implicate XBP-1 s dysregulation in MM pathogenesis.