title: Immunohistochemical analysis of NOTCH1 and JAGGED1 expression in multiple myeloma and monoclonal gammopathy of undetermined significance.
abstract: Notch signaling is implicated in the pathogenesis of multiple myeloma expressing high level of active Notch proteins NOTCH1 and JAGGED1 in tumor plasma cells. We investigated expression of NOTCH1 and JAGGED1 in bone marrow trephine biopsies of 80 newly diagnosed multiple myeloma and 20 monoclonal gammopathy of undetermined significance patients using immunohistochemical methods. The number of positive tumor cells was counted per 1000 tumor cells and the intensity of staining was assessed semi quantitatively. Multiple myelomas expressed NOTCH1 in 92.31% (72/78) and JAGGED1 in 92.21% (71/77) cases. NOTCH1 staining was strong in the majority of cases (59.7%), whereas JAGGED1 was predominately weak (67.6% of cases). In contrast, both markers were negative in all monoclonal gammopathy of undetermined significance cases. However, upon progression of disease from monoclonal gammopathy of undetermined significance to multiple myeloma (seen in 4 patients), analysis of the subsequent bone marrow biopsy showed weak expression of both markers in tumorous plasma cells. Immunohistochemistry results were compared with the pattern of bone marrow infiltration, plasma cell differentiation, and the presence of t(11;14)(q13,q32), t(14;16)(q32;q23),and t(4;14)(p16.3;q23) and overall survival in multiple myeloma patients. A significant correlation was found between strong NOTCH1 staining in multiple myeloma plasma cells and the diffuse type of bone marrow infiltration (P = .002) and an immature morphologic type of plasma cells (P = .043). After a median follow-up of 20.3 months, in multiple myeloma patients no difference in overall survival between NOTCH1 (P = .484) and JAGGED1 (P = .822) positive and negative cases were found. In conclusion, our results indicate importance of NOTCH1 and JAGGED1 expression in plasma cell neoplasia and a possible diagnostic value of their immunohistochemical evaluation of bone marrow infiltrates for multiple myeloma.
authors.affiliation: Department of Pathology and Cytology, University of Zagreb, School of Medicine, University Hospital Merkur, Zagreb, Croatia. skrtic.anita@gmail.com
authors.forename: Anita
authors.initials: A
authors.lastname: Skrtić
authors.forename: Petra
authors.initials: P
authors.lastname: Korać
authors.forename: Delfa Radić
authors.initials: DR
authors.lastname: Krišto
authors.forename: Radmila
authors.initials: R
authors.lastname: Ajduković Stojisavljević
authors.forename: Davor
authors.initials: D
authors.lastname: Ivanković
authors.forename: Mara
authors.initials: M
authors.lastname: Dominis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D017523:Croatia / Q000453:epidemiology; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008875:Middle Aged; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D009101:Multiple Myeloma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D010950:Plasma Cells / Q000378:metabolism / Q000473:pathology; D051881:Receptor, Notch1 / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins