title: Opposite activation of the Hedgehog pathway in CD138+ plasma cells and CD138-CD19+ B cells identifies two subgroups of patients with multiple myeloma and different prognosis.
abstract: Hyperactivation of the Hedgehog (Hh) pathway, which controls refueling of multiple myeloma (MM) clones, might be critical to disease recurrence. Although several studies suggest the Hh pathway is activated in CD138- immature cells, differentiated CD138+ plasma cells might also be able to self-renew by producing themselves the Hh ligands. We studied the gene expression profiles of 126 newly diagnosed MM patients analyzed in both the CD138+ plasma cell fraction and CD138-CD19+ B-cell compartment. Results demonstrated that an Hh-gene signature was able to cluster patients in two subgroups characterized by the opposite Hh pathway expression in mature plasma cells and their precursors. Strikingly, patients characterized by Hh hyperactivation in plasma cells, but not in their B cells, displayed high genomic instability and an unfavorable outcome in terms of shorter progression-free survival (hazard ratio: 1.92; 95% confidence interval: 1.19-3.07) and overall survival (hazard ratio: 2.61; 95% confidence interval: 1.26-5.38). These results suggest that the mechanisms triggered by the Hh pathway ultimately led to identify a more indolent vs a more aggressive biological and clinical subtype of MM. Therefore, patient stratification according to their molecular background might help the fine-tuning of future clinical and therapeutic studies.
authors.affiliation: Institute of Haematology 'L. & A. Seràgnoli', Department of Experimental Diagnostic and Specialty Medicine (DIMES), Bologna University School of Medicine, Bologna, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Martello
authors.affiliation: Department of Physics and Astronomy (DIFA), University of Bologna, Bologna, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Remondini
authors.affiliation: Institute of Haematology 'L. & A. Seràgnoli', Department of Experimental Diagnostic and Specialty Medicine (DIMES), Bologna University School of Medicine, Bologna, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Borsi
authors.affiliation: Institute of Haematology 'L. & A. Seràgnoli', Department of Experimental Diagnostic and Specialty Medicine (DIMES), Bologna University School of Medicine, Bologna, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Santacroce
authors.affiliation: Institute of Haematology 'L. & A. Seràgnoli', Department of Experimental Diagnostic and Specialty Medicine (DIMES), Bologna University School of Medicine, Bologna, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Procacci
authors.affiliation: Institute of Haematology 'L. & A. Seràgnoli', Department of Experimental Diagnostic and Specialty Medicine (DIMES), Bologna University School of Medicine, Bologna, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Pezzi
authors.affiliation: Institute of Haematology 'L. & A. Seràgnoli', Department of Experimental Diagnostic and Specialty Medicine (DIMES), Bologna University School of Medicine, Bologna, Italy.
authors.forename: F A
authors.initials: FA
authors.lastname: Dico
authors.affiliation: Institute of Haematology 'L. & A. Seràgnoli', Department of Experimental Diagnostic and Specialty Medicine (DIMES), Bologna University School of Medicine, Bologna, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Martinelli
authors.affiliation: Institute of Haematology 'L. & A. Seràgnoli', Department of Experimental Diagnostic and Specialty Medicine (DIMES), Bologna University School of Medicine, Bologna, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Zamagni
authors.affiliation: Institute of Haematology 'L. & A. Seràgnoli', Department of Experimental Diagnostic and Specialty Medicine (DIMES), Bologna University School of Medicine, Bologna, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Tacchetti
authors.affiliation: Institute of Haematology 'L. & A. Seràgnoli', Department of Experimental Diagnostic and Specialty Medicine (DIMES), Bologna University School of Medicine, Bologna, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Pantani
authors.affiliation: Institute of Haematology 'L. & A. Seràgnoli', Department of Experimental Diagnostic and Specialty Medicine (DIMES), Bologna University School of Medicine, Bologna, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Testoni
authors.affiliation: Institute of Haematology 'L. & A. Seràgnoli', Department of Experimental Diagnostic and Specialty Medicine (DIMES), Bologna University School of Medicine, Bologna, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Marzocchi
authors.affiliation: Institute of Haematology 'L. & A. Seràgnoli', Department of Experimental Diagnostic and Specialty Medicine (DIMES), Bologna University School of Medicine, Bologna, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Rocchi
authors.affiliation: Institute of Haematology 'L. & A. Seràgnoli', Department of Experimental Diagnostic and Specialty Medicine (DIMES), Bologna University School of Medicine, Bologna, Italy.
authors.forename: B A
authors.initials: BA
authors.lastname: Zannetti
authors.affiliation: Institute of Haematology 'L. & A. Seràgnoli', Department of Experimental Diagnostic and Specialty Medicine (DIMES), Bologna University School of Medicine, Bologna, Italy.
authors.forename: K
authors.initials: K
authors.lastname: Mancuso
authors.affiliation: Institute of Haematology 'L. & A. Seràgnoli', Department of Experimental Diagnostic and Specialty Medicine (DIMES), Bologna University School of Medicine, Bologna, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Cavo
authors.affiliation: Institute of Haematology 'L. & A. Seràgnoli', Department of Experimental Diagnostic and Specialty Medicine (DIMES), Bologna University School of Medicine, Bologna, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Terragna
mesh_terms: D000818:Animals; D018941:Antigens, CD19; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D053823:Hedgehog Proteins / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000175:diagnosis* / Q000276:immunology / Q000378:metabolism; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D015398:Signal Transduction; D053668:Syndecan-1; D014407:Tumor Cells, Cultured
chemical_list: D018941:Antigens, CD19; C000604811:CD19 molecule, human; D053823:Hedgehog Proteins; C508241:SDC1 protein, human; D053668:Syndecan-1