title: Multiple myeloma-derived Jagged ligands increases autocrine and paracrine interleukin-6 expression in bone marrow niche.
abstract: Multiple myeloma cell growth relies on intrinsic aggressiveness, due to a high karyotypic instability, or on the support from bone marrow (BM) niche.We and other groups have provided evidences that Notch signaling is related to tumor cell growth, pharmacological resistance, localization/recirculation in the BM and bone disease.This study indicates that high gene expression levels of Notch signaling members (JAG1, NOTCH2, HES5 and HES6) correlate with malignant progression or high-risk disease, and Notch signaling may participate in myeloma progression by increasing the BM levels of interleukin-6 (IL-6), a major player in myeloma cell growth and survival. Indeed, in vitro results, confirmed by correlation analysis on gene expression profiles of myeloma patients and immunohistochemical studies, demonstrated that Notch signaling controls IL-6 gene expression in those myeloma cells capable of IL-6 autonomous production as well as in surrounding BM stromal cells. In both cases Notch signaling activation may be triggered by myeloma cell-derived Jagged ligands. The evidence that Notch signaling positively controls IL-6 in the myeloma-associated BM makes this pathway a key mediator of tumor-directed reprogramming of the bone niche.This work strengthens the rationale for a novel Notch-directed therapy in multiple myeloma based on the inhibition of Jagged ligands.
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Colombo
authors.affiliation: Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Hematology, Fondazione Cà Granda IRCCS Policlinico, Milano, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Galletti
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, Milano, Italy.|Unit of Pathology A.O. San Paolo, Milan, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Bulfamante
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, Milano, Italy.|Unit of Pathology A.O. San Paolo, Milan, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Falleni
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, Milano, Italy.|Unit of Pathology A.O. San Paolo, Milan, Italy.
authors.forename: Delfina
authors.initials: D
authors.lastname: Tosi
authors.affiliation: Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Todoerti
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, Milano, Italy.|Department of Medicine, Division of Regenerative Medicine, Moores Cancer Center at University of California, San Diego, La Jolla, CA, USA.|Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: Lazzari
authors.affiliation: Department of Medicine, Division of Regenerative Medicine, Moores Cancer Center at University of California, San Diego, La Jolla, CA, USA.|Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Crews
authors.affiliation: Department of Medicine, Division of Regenerative Medicine, Moores Cancer Center at University of California, San Diego, La Jolla, CA, USA.|Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
authors.forename: Catriona H M
authors.initials: CH
authors.lastname: Jamieson
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Ravaioli
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Baccianti
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Garavelli
authors.affiliation: Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Hematology, Fondazione Cà Granda IRCCS Policlinico, Milano, Italy.
authors.forename: Natalia
authors.initials: N
authors.lastname: Platonova
authors.affiliation: Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Hematology, Fondazione Cà Granda IRCCS Policlinico, Milano, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Neri
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Chiaramonte
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001853:Bone Marrow / Q000473:pathology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D018450:Disease Progression; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D000072100:Jagged-1 Protein / Q000235:genetics / Q000378:metabolism; D000072101:Jagged-2 Protein / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015850:Interleukin-6; D000072100:Jagged-1 Protein; D000072101:Jagged-2 Protein; D008024:Ligands; D034741:RNA, Small Interfering; D051880:Receptors, Notch; D012097:Repressor Proteins; C411859:HES6 protein, human; C508600:IL6 protein, human; C000606273:JAG1 protein, human; C490504:JAG2 protein, human; C077478:HES5 protein, human
keywords: Jagged; Notch signaling; Pathology Section; bone marrow niche; interleukin-6; multiple myeloma