E-GEOD-6980 - Transcription profiling of mouse multiple myeloma tumors and splenic B cells from transgenics overexpressing XBP-1s
Submitted on 7 February 2007, released on 6 November 2007, last updated on 27 March 2012
Multiple myeloma (MM) evolves from highly prevalent premalignant condition termed Monoclonal Gammopathy of Undetermined Significance (MGUS). We report an MGUS-MM phenotype arising in transgenic mice with Emu-directed expression of the unfolded protein/ER stress response and plasma cell development spliced isoform factor XBP-1s. Emu-XBP-1s elicited elevated serum Ig and IL-6 levels, skin alterations and with advancing age, a significant proportion of Emu-xbp-1s transgenic mice develop features diagnostic of human MM including bone lytic lesions. Transcriptional profiles of Emu-xbp-1s B lymphoid and MM cells show aberrant expression of genes known to be dysregulated in human MM including Cyclin D1, MAF, MAFB, and APRIL. This genetic model coupled with documented frequent XBP-1s overexpression in human MM serve to implicate chronic XBP-1s dysregulation in the development of this common and lethal malignancy. Experiment Overall Design: In this study, we have explored the biological impact of sustained XBP-1s expression in the lymphoid system, anticipating that this genetic event would be a necessary component along with other MM-relevant oncogenes and tumor suppressor gene manipulations to generate a MM-prone mouse model. Unexpectedly, XBP-1s overexpression alone yielded an MGUS-MM disease bearing many features classical of the human disease on the clinical, pathological and molecular levels. Experiment Overall Design: We performed expression analysis of B cells derived from the spleen of 20-week old Emu-xbp-1s mice (n=5) and non-transgenic mice (n=5). Additionally, we analyzed the expression profiles from MM tumor cells arising in Emu-xbp-1s mice (n=6).
transcription profiling by array, co-expression, strain or line
The differentiation and stress response factor XBP-1 drives multiple myeloma pathogenesis. Daniel R Carrasco, Kumar Sukhdeo, Marina Protopopova, Raktim Sinha, Miriam Enos, Daniel E Carrasco, Mei Zheng, Mala Mani, Joel Henderson, Geraldine S Pinkus, Nikhil Munshi, James Horner, Elena V Ivanova, Alexei Protopopov, Kenneth C Anderson, Giovanni Tonon, Ronald A DePinho. Cancer Cell 11(4):349-60 (2007)