title: High expression of endoplasmic reticulum chaperone grp94 is a novel molecular hallmark of malignant plasma cells in multiple myeloma.
abstract: BACKGROUND
  Multiple myeloma (MM) is a hematologic malignancy that is characterized by the proliferation of abnormal bone marrow plasma cells (BMPC) and overproduction of immunoglobulin or light chains with evidence of end-organ damage such as bone damage, anemia, hypercalcemia, and renal dysfunction. The pathogenesis of MM is closely linked to dysregulated unfolded protein response (UPR) in the endoplasmic reticulum (ER). Constitutive activation of UPR in mice, as demonstrated by transgenic expression of a master UPR transcription factor XBP1s (a UPR-specific splice variant of X-box binding protein 1), causes myeloma. grp94 (gp96) is a key downstream chaperone in the ER that mediates the UPR as a part of the protein quality control mechanism in the secretory pathway. Our recent study has shown that the persistence of plasma cells as well as the development of myeloma in XBP1s-transgenic mice is critically dependent on grp94. However, the role of grp94 in the initiation and progression of human MM is still unknown.
  
  
  METHODS
  The expression level of grp94 in BMPCs was measured by flow cytometry, real-time RT-PCR, and Western blot analysis. We compared the expression levels of grp94 in BMPCs in a spectrum of patients including MM, monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM), as well as non-plasma cell disorders (NPC).
  
  
  RESULTS
  We found that grp94 was highly expressed in malignant plasma cells in patients with MM, but not in BMPCs in patients with MGUS/SMM and NPC. The expression level of grp94 correlated significantly with CD138 expression level. We also found that the grp94 expression level in BMPCs from International Staging System (ISS) stage III MM patients is higher than those in ISS stage I/II MM patients.
  
  
  CONCLUSIONS
  grp94 is highly expressed in BMPCs in MM, which correlates with the advanced stage of this disease. Our data demonstrated that grp94 is a novel diagnostic and prognostic biomarker. It also positioned grp94 as a promising therapeutic target for MM.
authors.affiliation: Hollings Cancer Center, 86 Jonathan Lucas Street, Charleston, SC, 29425, USA. chhabra@musc.edu.|Division of Hematology and Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425, USA. chhabra@musc.edu.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Chhabra
authors.affiliation: Hollings Cancer Center, 86 Jonathan Lucas Street, Charleston, SC, 29425, USA. jaisa@musc.edu.|Division of Hematology and Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425, USA. jaisa@musc.edu.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Jain
authors.affiliation: Hollings Cancer Center, 86 Jonathan Lucas Street, Charleston, SC, 29425, USA. wallacc@musc.edu.|Department of Microbiology and Immunology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC, 29425, USA. wallacc@musc.edu.
authors.forename: Caroline
authors.initials: C
authors.lastname: Wallace
authors.affiliation: Hollings Cancer Center, 86 Jonathan Lucas Street, Charleston, SC, 29425, USA. hongf@musc.edu.|Department of Microbiology and Immunology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC, 29425, USA. hongf@musc.edu.
authors.forename: Feng
authors.initials: F
authors.lastname: Hong
authors.affiliation: Hollings Cancer Center, 86 Jonathan Lucas Street, Charleston, SC, 29425, USA. liube@musc.edu.|Department of Microbiology and Immunology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC, 29425, USA. liube@musc.edu.
authors.forename: Bei
authors.initials: B
authors.lastname: Liu
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000276:immunology* / Q000473:pathology; D010950:Plasma Cells / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor