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 Emu-directed expression of the XBP-1 spliced isoform (XBP-1s), a factor governing unfolded protein/ER stress response and plasma-cell development. Emu-XBP-1s elicited elevated serum Ig and skin alterations. With age, Emu-xbp-1s transgenics develop features diagnostic of human MM, including bone lytic lesions and subendothelial Ig deposition. Furthermore, transcriptional profiles of Emu-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.
Carrasco
Daniel R
DR
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, and Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA. ruben_carrasco@dfci.harvard.edu
Sukhdeo
Kumar
K
Protopopova
Marina
M
Sinha
Raktim
R
Enos
Miriam
M
Carrasco
Daniel E
DE
Zheng
Mei
M
Mani
Mala
M
Henderson
Joel
J
Pinkus
Geraldine S
GS
Munshi
Nikhil
N
Horner
James
J
Ivanova
Elena V
EV
Protopopov
Alexei
A
Anderson
Kenneth C
KC
Tonon
Giovanni
G
DePinho
Ronald A
RA
D000375:Aging / Q000473:pathology; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D001847:Bone Diseases / Q000473:pathology; D002454:Cell Differentiation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020312:Dromaiidae / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D006942:Hypergammaglobulinemia / Q000473:pathology; D007674:Kidney Diseases / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010950:Plasma Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D012326:RNA Splicing; D000071701:Regulatory Factor X Transcription Factors; D012871:Skin Diseases / Q000473:pathology; D014157:Transcription Factors; D014158:Transcription, Genetic; D000071717:X-Box Binding Protein 1
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse