(Cell Press, 2007) Carrasco, Daniel R.; Sukhdeo, Kumar; Protopopova, Marina; Enos, Miriam; Zheng, Mei; Mani, Mala; Ivanova, Elena V.; Tonon, Giovanni; Sinha, Raktim; Carrasco, Daniel E.; Henderson, Joel; Pinkus, Geraldine; Munshi, Nikhil; Horner, James W.; Protopopov, Alexei; Anderson, Kenneth; DePinho, Ronald A.
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 Eμ-directed expression of the XBP-1 spliced isoform (XBP-1s), a factor governing unfolded protein/ER stress response and plasma-cell development. Eμ-XBP-1s elicited elevated serum Ig and skin alterations. With age, Eμ-xbp-1s transgenics develop features diagnostic of human MM, including bone lytic lesions and subendothelial Ig deposition. Furthermore, transcriptional profiles of Eμ-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-1s overexpression in human MM, serve to implicate XBP-1s dysregulation in MM pathogenesis.
