title: XBP1s levels are implicated in the biology and outcome of myeloma mediating different clinical outcomes to thalidomide-based treatments.
abstract: Immunoglobulin production by myeloma plasma cells depends on the unfolded protein response for protein production and folding. Recent studies have highlighted the importance of IRE1alpha 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 IRE1alpha, XBP1, XBP1UNSPLICED (XBP1u), and XBP1SPLICED (XBP1s) in a series of patients with myeloma and correlated findings with clinical outcome. We show that IRE1alpha 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 beta2 microglobulin and t(4;14) to identify a group of patients with a poor outcome. Furthermore, 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.
authors.affiliation: Section of Haemato-Oncology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, UK.
authors.forename: Tina
authors.initials: T
authors.lastname: Bagratuni
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.forename: David
authors.initials: D
authors.lastname: Gonzalez de Castro
authors.forename: Emma L
authors.initials: EL
authors.lastname: Davenport
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Dickens
authors.forename: Brian A
authors.initials: BA
authors.lastname: Walker
authors.forename: Kevin
authors.initials: K
authors.lastname: Boyd
authors.forename: David C
authors.initials: DC
authors.lastname: Johnson
authors.forename: Walter
authors.initials: W
authors.lastname: Gregory
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Morgan
authors.forename: Faith E
authors.initials: FE
authors.lastname: Davies
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D003907:Dexamethasone / Q000008:administration & dosage / Q000627:therapeutic use; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008558:Melphalan / Q000627:therapeutic use; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011241:Prednisone / Q000627:therapeutic use; D011379:Prognosis; D016016:Proportional Hazards Models; D000071701:Regulatory Factor X Transcription Factors; D013792:Thalidomide / Q000627:therapeutic use*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014750:Vincristine / Q000627:therapeutic use; D000071717:X-Box Binding Protein 1
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D013792:Thalidomide; D014750:Vincristine; D003907:Dexamethasone; D004317:Doxorubicin; D003520:Cyclophosphamide; D008558:Melphalan; D011241:Prednisone