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

doi:10.1016/j.ccr.2007.02.015

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

Cancer Cell. 2007 Apr;11(4):349-60. doi: 10.1016/j.ccr.2007.02.015.

Authors

Daniel R Carrasco¹, 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

Affiliation

¹ 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

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aging / pathology
Animals
B-Lymphocytes / metabolism
B-Lymphocytes / pathology
Bone Diseases / pathology
Cell Differentiation*
Cells, Cultured
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Dromaiidae / genetics
Electrophoretic Mobility Shift Assay
Endoplasmic Reticulum / metabolism
Endoplasmic Reticulum / pathology*
Female
Humans
Hypergammaglobulinemia / pathology
Kidney Diseases / pathology
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Multiple Myeloma / metabolism
Multiple Myeloma / pathology*
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Plasma Cells / cytology*
Plasma Cells / immunology
Plasma Cells / metabolism
RNA Splicing
Regulatory Factor X Transcription Factors
Skin Diseases / pathology
Transcription Factors
Transcription, Genetic
X-Box Binding Protein 1

Substances

DNA-Binding Proteins
Nuclear Proteins
Regulatory Factor X Transcription Factors
Transcription Factors
X-Box Binding Protein 1
XBP1 protein, human
Xbp1 protein, mouse

Associated data

GEO/GSE6980

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding