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The Differentiation and Stress Response Factor XBP-1 Drives Multiple Myeloma Pathogenesis

2007; Cell Press; Volume: 11; Issue: 4 Linguagem: Inglês

10.1016/j.ccr.2007.02.015

1878-3686

Daniel R. Carrasco, Kumar Sukhdeo, Marina Protopopova, Raktim Sinha, Miriam Enos, Daniel E. Carrasco, Mei Zheng, Mala Mani, Joel Henderson, Geraldine S. Pinkus, Nikhil C. Munshi, James W. Horner, Elena Ivanova, Alexei Protopopov, Kenneth C. Anderson, Giovanni Tonon, Ronald A. DePinho,

Endoplasmic Reticulum Stress and Disease

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.