The differentiation and stress response factor XBP-1 drives multiple myeloma pathogenesis (Cancer Cell, 2007, 11:349-360)

報告日期: 2007/11/09
報告時間: 15:10/16:00
報告學生: 黃薇靜
講評老師: 蔣輯武
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The Differentiation and Stress Response Factor XBP-1 Drives Multiple Myeloma Pathogenesis

Carrasco et al., Cancer Cell, 11: 349-360, 2007

Student: 黃薇靜

Commentator: 蔣輯武 博士

Time: 15:10-16:00, Nov 9, 2007

Place: Room 602

Abstract

Multiple myeloma (MM) is a B cell neoplasm characterized by serum monoclonal gammopathy and osteolytic bone lesions. It is preceded by an age-dependent premalignant condition termed monoclonal gammopathy of undetermined significance (MGUS).1 MGUS cells secrete monoclonal immunoglobulin (Ig) and progress to malignant MM at a rate of 1-3% per year. However, the molecular mechanisms underlying the malignant transformation of MGUS are unknown. Despite improvements in treatment including high-dose chemotherapy and transplantation, the disease remains incurable. Previous studies have identified a spliced form of transcription factor X-box binding protein I (XBP-1) to be essential for the differentiation of plasma cells and the unfolded protein/ER stress response.2 XBP-1 overexpression was detected in human MM cells and its abundant expression can be selectively induced by IL-6, a growth factor for malignant plasma cells. In this study, the authors generated a transgenic mice with Em-directed expression of the XBP-1 spliced isoform (XBP-1s) in B cells and plasma cells. The transgenic mice manifested skin and renal alterations resembling patients with chronic plasma-cell disorders. With age, hypergammaglobulinemia, bone marrow plasmacytic infiltrates, and bone lytic lesions were also observed in the transgenic mice. The spontaneous progression from MGUS to MM in the Em-xbp-1s transgenic mice clinically mirrors disease progression in the human. Furthermore, transcriptome profiling was performed to compare the gene expression of Em-xbp-1s B cells and tumor plasma cells. Therefore, the authors provide genetic evidence and correlative human data to support the role of XBP-1s dysregulation leading to MGUS transformation and MM pathogenesis. XBP-1s expression suggested chronic cellular stress may contribute to MM progression.3 Based on the results obtained from this study, the Em-xbp-1s transgenic mice may be a potential preclinical model for assessing new therapeutic strategies.

 

References

1. Kuehl and Bergsagel, Multiple myeloma: Evolving genetic events and host interactions. Nat. Rev. Cancer 2: 175-187, 2002

2. Iwakoshi et al., Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1. Nat. Immunol. 4: 321-329, 2003

3. Sirohi and Powles, Epidemiology and outcomes research for MGUS, myeloma and amyloidosis. Eur. J. Cancer 42: 1671-1683, 2006