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

DR Carrasco, K Sukhdeo, M Protopopova, R Sinha… - Cancer cell, 2007 - cell.com
DR Carrasco, K Sukhdeo, M Protopopova, R Sinha, M Enos, DE Carrasco, M Zheng, M Mani…
Cancer cell, 2007cell.com
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 …
Summary
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 -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.
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