title: The sialyltransferase ST3GAL6 influences homing and survival in multiple myeloma.
abstract: Glycosylation is a stepwise procedure of covalent attachment of oligosaccharide chains to proteins or lipids, and alterations in this process, especially increased sialylation, have been associated with malignant transformation and metastasis. The role of altered sialylation in multiple myeloma (MM) cell trafficking has not been previously investigated. In the present study we identified high expression of β-galactoside α-2,3-sialyltransferase, ST3GAL6, in MM cell lines and patients. This gene plays a key role in selectin ligand synthesis in humans through the generation of functional sialyl Lewis X. In MRC IX patients, high expression of this gene is associated with inferior overall survival. In this study we demonstrate that knockdown of ST3GAL6 results in a significant reduction in levels of α-2,3-linked sialic acid on the surface of MM cells with an associated significant reduction in adhesion to MM bone marrow stromal cells and fibronectin along with reduced transendothelial migration in vitro. In support of our in vitro findings, we demonstrate significantly reduced homing and engraftment of ST3GAL6 knockdown MM cells to the bone marrow niche in vivo, along with decreased tumor burden and prolonged survival. This study points to the importance of altered glycosylation, particularly sialylation, in MM cell adhesion and migration.
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Department of Hematology, National University of Ireland, Galway and Galway University Hospital, Galway, Ireland;
authors: Siobhan V
authors: SV
authors: Glavey
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors: Salomon
authors: S
authors: Manier
authors: Department of Hematology, National University of Ireland, Galway and Galway University Hospital, Galway, Ireland;
authors: Alessandro
authors: A
authors: Natoni
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors: Antonio
authors: A
authors: Sacco
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors: Michele
authors: M
authors: Moschetta
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors: Michaela R
authors: MR
authors: Reagan
authors: Department of Hematology, National University of Ireland, Galway and Galway University Hospital, Galway, Ireland;
authors: Laura S
authors: LS
authors: Murillo
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors: Ilyas
authors: I
authors: Sahin
authors: Centre for Myeloma Research, Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom; and.
authors: Ping
authors: P
authors: Wu
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors: Yuji
authors: Y
authors: Mishima
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors: Yu
authors: Y
authors: Zhang
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors: Wenjing
authors: W
authors: Zhang
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors: Yong
authors: Y
authors: Zhang
authors: Centre for Myeloma Research, Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom; and.
authors: Gareth
authors: G
authors: Morgan
authors: Glycoscience Research Group, National University of Ireland, Galway, Ireland.
authors: Lokesh
authors: L
authors: Joshi
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors: Aldo M
authors: AM
authors: Roccaro
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors: Irene M
authors: IM
authors: Ghobrial
authors: Department of Hematology, National University of Ireland, Galway and Galway University Hospital, Galway, Ireland; Glycoscience Research Group, National University of Ireland, Galway, Ireland.
authors: Michael E
authors: ME
authors: O'Dwyer
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000201:enzymology / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D019158:N-Acetylneuraminic Acid / Q000096:biosynthesis / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D012799:Sialyltransferases / Q000235:genetics / Q000378:metabolism*; D017154:Stromal Cells / Q000201:enzymology / Q000473:pathology; D057705:Transendothelial and Transepithelial Migration; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase
chemical_list: D009363:Neoplasm Proteins; D012799:Sialyltransferases; D019158:N-Acetylneuraminic Acid; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase