XBP1s levels are implicated in the biology and outcome of myeloma mediating different clinical outcomes to thalidomide-based treatments

被引：91

作者：

Bagratuni, Tina ^{[1
]}

Wu, Ping ^{[1
]}

de Castro, David Gonzalez ^{[1
]}

Davenport, Emma L. ^{[1
]}

Dickens, Nicholas J. ^{[1
]}

Walker, Brian A. ^{[1
]}

Boyd, Kevin ^{[1
]}

Johnson, David C. ^{[1
]}

Gregory, Walter ^{[2
]}

Morgan, Gareth J. ^{[1
]}

Davies, Faith E. ^{[1
]}

机构：

[1] Inst Canc Res, Sect Haematooncol, Sutton SM2 5NG, Surrey, England

[2] Univ Leeds, Clin Trials & Res Unit, Leeds, W Yorkshire, England

来源：

BLOOD | 2010年 / 116卷 / 02期

关键词：

UNFOLDED PROTEIN RESPONSE; B-CELL;

D O I：

10.1182/blood-2010-01-263236

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Immunoglobulin production by myeloma plasma cells depends on the unfolded protein response for protein production and folding. Recent studies have highlighted the importance of IRE1 alpha and X box binding protein 1 (XBP1), key members of this pathway, in normal B-plasma cell development. We have determined the gene expression levels of IRE1 alpha, XBP1, XBP1UNSPLICED (XBP1u), and XBP1SPLICED (XBP1s) in a series of patients with myeloma and correlated findings with clinical outcome. We show that IRE1 alpha and XBP1 are highly expressed and that patients with low XBP1s/u ratios have a significantly better overall survival. XBP1s is an independent prognostic marker and can be used with beta 2 microglobulin and t(4;14) to identify a group of patients with a poor outcome. Further-more, we show the beneficial therapeutic effects of thalidomide in patients with low XBP1s/u ratios. This study highlights the importance of XBP1 in myeloma and its significance as an independent prognostic marker and as a predictor of thalidomide response. This trial was registered at www.controlled-trials.com/ISRCTN68454111/68454111 as #ISRCTN684541111. (Blood. 2010; 116(2): 250-253)

引用

页码：250 / 253

页数：4

共 21 条

[1] Regulation of apoptosis by endoplasmic reticulum pathways [J].

Breckenridge, DG ;

Germain, M ;

Mathai, JP ;

Nguyen, M ;

Shore, GC .

ONCOGENE, 2003, 22 (53) :8608-8618

[2] B- and T-cell development both involve activity of the unfolded protein response pathway [J].

Brunsing, Ryan ;

Omori, Sidne A. ;

Weber, Frank ;

Bicknell, Alicia ;

Friend, Leslie ;

Rickert, Robert ;

Niwa, Maho .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (26) :17954-17961

[3] The differentiation and stress response factor XBP-1 drives multiple myeloma pathogenesis [J].

Carrasco, Daniel R. ;

Sukhdeo, Kumar ;

Protopopova, Marina ;

Sinha, Raktim ;

Enos, Miriam ;

Carrasco, Daniel E. ;

Zheng, Mei ;

Mani, Mala ;

Henderson, Joel ;

Pinkus, Geraldine S. ;

Munshi, Nikhil ;

Horner, James ;

Ivanova, Elena V. ;

Protopopov, Alexei ;

Anderson, Kenneth C. ;

Tonon, Giovanni ;

DePinho, Ronald A. .

CANCER CELL, 2007, 11 (04) :349-360

[4] Untangling the unfolded protein response [J].

Davenport, Emma L. ;

Morgan, Gareth J. ;

Davies, Faith E. .

CELL CYCLE, 2008, 7 (07) :865-869

[5] Heat shock protein inhibition is associated with activation of the unfolded protein response pathway in myeloma plasma cells [J].

Davenport, Emma L. ;

Moore, Hannah E. ;

Dunlop, Alan S. ;

Sharp, Swee Y. ;

Workman, Paul ;

Morgan, Gareth J. ;

Davies, Faith E. .

BLOOD, 2007, 110 (07) :2641-2649

[6] Insights into the multistep transformation of MGUS to myeloma using microarray expression analysis [J].

Davies, FE ;

Dring, AM ;

Li, C ;

Rawstron, AC ;

Shammas, MA ;

O'Connor, SM ;

Fenton, JAL ;

Hideshima, T ;

Chauhan, D ;

Tai, IT ;

Robinson, E ;

Auclair, D ;

Rees, K ;

Gonzalez, D ;

Ashcroft, AJ ;

Dasgupta, R ;

Mitsiades, C ;

Mitsiades, N ;

Chen, LB ;

Wong, WH ;

Munshi, NC ;

Morgan, GJ ;

Anderson, KC .

BLOOD, 2003, 102 (13) :4504-4511

[7] Comparison of gene expression profiling between malignant and normal plasma cells with oligonucleotide arrays [J].

De Vos, J ;

Thykjær, T ;

Tarte, K ;

Ensslen, M ;

Raynaud, P ;

Requirand, G ;

Pellet, F ;

Pantesco, V ;

Rème, T ;

Jourdan, M ;

Rossi, JF ;

Orntoft, T ;

Klein, B .

ONCOGENE, 2002, 21 (44) :6848-6857

[8] Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications [J].

Gupta, D ;

Treon, SP ;

Shima, Y ;

Hideshima, T ;

Podar, K ;

Tai, YT ;

Lin, B ;

Lentzsch, S ;

Davies, FE ;

Chauhan, D ;

Schlossman, RL ;

Richardson, P ;

Ralph, P ;

Wu, L ;

Payvandi, F ;

Muller, G ;

Stirling, DI ;

Anderson, KC .

LEUKEMIA, 2001, 15 (12) :1950-1961

[9] Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase [J].

Harding, HP ;

Zhang, YH ;

Ron, D .

NATURE, 1999, 397 (6716) :271-274

[10] Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy [J].

Hideshima, T ;

Chauhan, D ;

Shima, Y ;

Raje, N ;

Davies, FE ;

Tai, YT ;

Treon, SP ;

Lin, B ;

Schlossman, RL ;

Richardson, P ;

Muller, G ;

Stirling, DI ;

Anderson, KC .

BLOOD, 2000, 96 (09) :2943-2950

← 1 2 3 →