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• W2794128825 abstract "Fucosylation is a biological process broadly observed in vertebrates, invertebrates, plants, bacteria, and fungi. Fucose moieties on cell-surface glycans are increasingly recognized as critical to many cell-cell interaction and signaling processes. One of the characteristic roles of fucose is its regulation of selectin-dependent leukocyte adhesion that has been well studied over the last two decades. Recent studies of fucose in immune cell development and function regulation have significantly expanded the contemporary understanding of fucosylation. From cellular adhesion to immune regulation, herein we discuss the use of gene knockout studies, competitive inhibitors of fucose-containing glycan, and metabolic inhibitors of fucose biosynthesis to probe fucosylated glycan biosynthesis and signaling and its functional consequences. Promising clinical and preclinical applications in sickle cell disease, rheumatoid arthritis, tumor inhibition, metastasis prevention, antibody-dependent cell-mediated cytotoxicity, chemoresistance reversal, and in improving chemotherapy-related side effects and recovery are reviewed. Fucosylation is a biological process broadly observed in vertebrates, invertebrates, plants, bacteria, and fungi. Fucose moieties on cell-surface glycans are increasingly recognized as critical to many cell-cell interaction and signaling processes. One of the characteristic roles of fucose is its regulation of selectin-dependent leukocyte adhesion that has been well studied over the last two decades. Recent studies of fucose in immune cell development and function regulation have significantly expanded the contemporary understanding of fucosylation. From cellular adhesion to immune regulation, herein we discuss the use of gene knockout studies, competitive inhibitors of fucose-containing glycan, and metabolic inhibitors of fucose biosynthesis to probe fucosylated glycan biosynthesis and signaling and its functional consequences. Promising clinical and preclinical applications in sickle cell disease, rheumatoid arthritis, tumor inhibition, metastasis prevention, antibody-dependent cell-mediated cytotoxicity, chemoresistance reversal, and in improving chemotherapy-related side effects and recovery are reviewed. Glycosylation is an enzymatic process in which glycosidic linkages are formed between saccharides and other saccharides, peptides, and lipids. The products of this process are a highly heterogeneous repertoire of glycans termed the glycome. Compared with genomics and proteomics, glycomics remains an enigmatic field of biology due to its non-templated structure and relative lack of investigative tools and enabling methods. L-fucose is a monosaccharide residue commonly found in glycans. Fucosylated carbohydrate moieties are involved in a wide variety of physiological and pathological processes including cell adhesion, tissue development, angiogenesis, fertilization, malignancy (Miyoshi et al., 2008Miyoshi E. Moriwaki K. Nakagawa T. Biological function of fucosylation in cancer biology.J. Biochem. 2008; 143: 725-729Crossref PubMed Scopus (233) Google Scholar), and tumor metastasis (Ma et al., 2006Ma B. Simala-Grant J.L. Taylor D.E. Fucosylation in prokaryotes and eukaryotes.Glycobiology. 2006; 16: 158R-184RCrossref PubMed Scopus (243) Google Scholar). Striking roles of fucosylation in immune cell development and functional regulation have been uncovered in the last decade and have significantly broadened the scope of fucosylation research. In addition, altered fucosylation has been observed in a number of inflammatory conditions, including rheumatoid arthritis (RA) (Brinkman-van der Linden et al., 1998Brinkman-van der Linden E.C. de Haan P.F. Havenaar E.C. van Dijk W. Inflammation-induced expression of sialyl LewisX is not restricted to alpha1-acid glycoprotein but also occurs to a lesser extent on alpha1-antichymotrypsin and haptoglobin.Glycoconjugate J. 1998; 15: 177-182Crossref PubMed Scopus (0) Google Scholar, Goodarzi et al., 1998Goodarzi M.T. Axford J.S. Varanasi S.S. Alavi A. Cunnane G. Fitzgerald O. Turner G.A. Sialyl Lewis(x) expression on IgG in rheumatoid arthritis and other arthritic conditions: a preliminary study.Glycoconj. J. 1998; 15: 1149-1154Crossref PubMed Scopus (12) Google Scholar, Li et al., 2014Li J. Hsu H.C. Ding Y. Li H. Wu Q. Yang P. Luo B. Rowse A.L. Spalding D.M. Bridges Jr., S.L. et al.Inhibition of fucosylation reshapes inflammatory macrophages and suppresses type II collagen-induced arthritis.Arthritis Rheumatol. 2014; 66: 2368-2379Crossref PubMed Scopus (15) Google Scholar, Ryden et al., 2002Ryden I. Pahlsson P. Lundblad A. Skogh T. Fucosylation of α1-acid glycoprotein (orosomucoid) compared with traditional biochemical markers of inflammation in recent onset rheumatoid arthritis.Clin. Chim. Acta. 2002; 317: 221-229Crossref PubMed Scopus (0) Google Scholar, Thompson et al., 1989Thompson S. Kelly C.A. Griffiths I.D. Turner G.A. Abnormally-fucosylated serum haptoglobins in patients with inflammatory joint disease.Clin. Chim. Acta. 1989; 184: 251-258Crossref PubMed Google Scholar), chronic pancreatitis (Sarrats et al., 2010Sarrats A. Saldova R. Pla E. Fort E. Harvey D.J. Struwe W.B. de Llorens R. Rudd P.M. Peracaula R. Glycosylation of liver acute-phase proteins in pancreatic cancer and chronic pancreatitis.Proteomics Clin. Appl. 2010; 4: 432-448Crossref PubMed Google Scholar), Crohn disease (Miyoshi et al., 2011Miyoshi J. Yajima T. Okamoto S. Matsuoka K. Inoue N. Hisamatsu T. Shimamura K. Nakazawa A. Kanai T. Ogata H. et al.Ectopic expression of blood type antigens in inflamed mucosa with higher incidence of FUT2 secretor status in colonic Crohn's disease.J. Gastroenterol. 2011; 46: 1056-1063Crossref PubMed Scopus (0) Google Scholar), and sclerosing cholangitis (Maroni et al., 2015Maroni L. van de Graaf S.F. Hohenester S.D. Oude Elferink R.P. Beuers U. Fucosyltransferase 2: a genetic risk factor for primary sclerosing cholangitis and Crohn's disease–a comprehensive review.Clin Rev Allergy Immunol. 2015; 48: 182-191Crossref PubMed Scopus (0) Google Scholar). Sickle cell disease provides a further example of benefit by modulation of fucose-dependent processes (Chang et al., 2010Chang J. Patton J.T. Sarkar A. Ernst B. Magnani J.L. Frenette P.S. GMI-1070, a novel pan-selectin antagonist, reverses acute vascular occlusions in sickle cell mice.Blood. 2010; 116: 1779-1786Crossref PubMed Scopus (131) Google Scholar). These findings have prompted the development of fucosylation inhibitors, including orally active inhibitors (Allen et al., 2016Allen J.G. Mujacic M. Frohn M.J. Pickrell A.J. Kodama P. Bagal D. San Miguel T. Sickmier E.A. Osgood S. Swietlow A. et al.Facile modulation of antibody fucosylation with small molecule fucostatin inhibitors and cocrystal structure with GDP-mannose 4,6-dehydratase.ACS Chem. Biol. 2016; 11: 2734-2743Crossref PubMed Scopus (13) Google Scholar, Okeley et al., 2013Okeley N.M. Alley S.C. Anderson M.E. Boursalian T.E. Burke P.J. Emmerton K.M. Jeffrey S.C. Klussman K. Law C.-L. Sussman D. et al.Development of orally active inhibitors of protein and cellular fucosylation.Proc. Natl. Acad. Sci. USA. 2013; 110: 5404-5409Crossref PubMed Scopus (65) Google Scholar, Rillahan et al., 2012Rillahan C.D. Antonopoulos A. Lefort C.T. Sonon R. Azadi P. Ley K. Dell A. Haslam S.M. Paulson J.C. Global metabolic inhibitors of sialyl- and fucosyltransferases remodel the glycome.Nat. Chem. Biol. 2012; 8: 661-668Crossref PubMed Scopus (158) Google Scholar, Tu et al., 2013Tu Z. Lin Y.N. Lin C.H. Development of fucosyltransferase and fucosidase inhibitors.Chem. Soc. Rev. 2013; 42: 4459-4475Crossref PubMed Scopus (18) Google Scholar), as novel therapeutic strategies in fucosylation-associated diseases. Much of the biology of fucosylation has been studied using genetic engineering, selective inhibitors of glycan fucosylation, and competitive inhibitors of fucose-dependent binding. In this review, we explore and assess recently revealed roles of fucosylation in diseases and in processes from cell adhesion to immune system regulation. Fucosyltransferases (FUTs) are enzymes that catalyze the transfer of a fucose residue from the guanosine diphosphate (GDP)-fucose donor to acceptor molecules. Thirteen FUT genes have been identified in humans (Becker and Lowe, 2003Becker D.J. Lowe J.B. Fucose: biosynthesis and biological function in mammals.Glycobiology. 2003; 13: 41R-53RCrossref PubMed Scopus (515) Google Scholar). These FUTs catalyze α(1,2)-, α(1,3/4)-, α(1,6)-, and O-fucosylation (Figure 1A). The α(1,2)- and α(1,3/4)-FUTs catalyze terminal or sub-terminal fucosylation of acceptor molecules, whereas (1,6)-FUTs catalyze core fucosylation that occurs at the innermost moiety of N-glycan. O-Fucosylation, regulated by POFUT1/2, is the direct O-linkage of fucose to serine and threonine residues in epidermal growth factor (EGF)-like and thrombospondin type 1 repeat domains (Becker and Lowe, 2003Becker D.J. Lowe J.B. Fucose: biosynthesis and biological function in mammals.Glycobiology. 2003; 13: 41R-53RCrossref PubMed Scopus (515) Google Scholar, Ma et al., 2006Ma B. Simala-Grant J.L. Taylor D.E. Fucosylation in prokaryotes and eukaryotes.Glycobiology. 2006; 16: 158R-184RCrossref PubMed Scopus (243) Google Scholar). The selectins are the canonical binders of these fucose-containing glycans. Many glycan structures important in cell-cell interactions and regulation contain fucose. The ABO blood group antigen determinants, sialyl-Lewisa, sialyl-Lewisx, sialyl-Lewisy, and VIM-2 selectin ligands (Becker and Lowe, 2003Becker D.J. Lowe J.B. Fucose: biosynthesis and biological function in mammals.Glycobiology. 2003; 13: 41R-53RCrossref PubMed Scopus (515) Google Scholar) are examples (Figures 1B and 1C). A lymphocyte cell surface molecule involved in organ-specific homing was identified in 1983 (Gallatin et al., 1983Gallatin W.M. Weissman I.L. Butcher E.C. A cell-surface molecule involved in organ-specific homing of lymphocytes.Nature. 1983; 304: 30-34Crossref PubMed Google Scholar). This adhesion molecule was later named L-selectin, the first of the selectin family to be described. The selectins are glycan-binding trans-membrane C-type lectin proteins that are important in cell recognition, signaling, and adhesion in the vascular system. There are three types of selectins, E-, L-, and P-selectin. E-selectin is rapidly induced in epithelial cells by inflammatory cytokines, L-selectin is expressed on most lymphocytes, and P-selectin occurs on the cell surface of activated endothelial cells and platelets. The roles of the selectins in leukocyte adhesion, migration, and trafficking were soon revealed. Selectins bind to sialyl-Lewisx on glycoproteins and glycolipids, including E-selectin ligand-1 (ESL-1), P-selectin glycoprotein ligand-1 (PSGL-1), mucosal vascular addressin cell adhesion molecule-1 (MAdCAM-1), glycosylation-dependent cell adhesion molecule-1 (GlyCAM-1), and CD34 on endothelium (Angiari and Constantin, 2013Angiari S. Constantin G. Selectins and their ligands as potential immunotherapeutic targets in neurological diseases.Immunotherapy. 2013; 5: 1207-1220Crossref PubMed Scopus (0) Google Scholar, Blankenberg et al., 2003Blankenberg S. Barbaux S. Tiret L. Adhesion molecules and atherosclerosis.Atherosclerosis. 2003; 170: 191-203Abstract Full Text Full Text PDF PubMed Scopus (766) Google Scholar). Selectins also bind to CD44, death receptor-3 (DR3), lysosomal-associated membrane proteins (LAMP1 and LAMP2), CD44v, gangliosides and glycosphingolipids on cancer cells (Gout et al., 2008Gout S. Trembley P.-L. Huot J. Selectins and selectin ligands in extravasation of cancer cells and organ selectivity of metastasis.Clin. Exp. Metastasis. 2008; 25: 335-344Crossref PubMed Scopus (86) Google Scholar), and pathogens (Gringhuis et al., 2014Gringhuis S.I. Kaptein T.M. Wevers B.A. van der Vlist M. Klaver E.J. van Die I. Vriend L.E. de Jong M.A. Geijtenbeek T.B. Fucose-based PAMPs prime dendritic cells for follicular T helper cell polarization via DC-SIGN-dependent IL-27 production.Nat. Commun. 2014; 5: 5074Crossref PubMed Scopus (21) Google Scholar). The carbohydrate selectin ligands are fucosylated structures. FUT4 and FUT7 are two α(1,3/4)-FUTs expressed in leukocytes and endothelia and catalyzing selectin ligand biosynthesis. By using a FUT gene deletion approach, Lowe's group has demonstrated the contributions of FUT4 and FUT7 to E-, P-, and L-selectin ligand synthesis and to the control of leukocyte recruitment and lymphocyte homing, in which FUT4 plays the major role (Homeister et al., 2001Homeister J.W. Thall A.D. Petryniak B. Maly P. Rogers C.E. Smith P.L. Kelly R.J. Gersten K.M. Askari S.W. Cheng G. et al.The alpha(1,3)fucosyltransferases FucT-IV and FucT-VII exert collaborative control over selectin-dependent leukocyte recruitment and lymphocyte homing.Immunity. 2001; 15: 115-126Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar, Knibbs et al., 1996Knibbs R.N. Craig R.A. Natsuka S. Chang A. Cameron M. Lowe J.B. Stoolman L.M. The fucosyltransferase FucT-VII regulates E-selectin ligand synthesis in human T cells.J. Cell Biol. 1996; 133: 911-920Crossref PubMed Scopus (0) Google Scholar, Maly et al., 1996Maly P. Thall A. Petryniak B. Rogers C.E. Smith P.L. Marks R.M. Kelly R.J. Gersten K.M. Cheng G. Saunders T.L. et al.The alpha(1,3)fucosyltransferase Fuc-TVII controls leukocyte trafficking through an essential role in L-, E-, and P-selectin ligand biosynthesis.Cell. 1996; 86: 643-653Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Wagers et al., 1996Wagers A.J. Lowe J.B. Kansas G.S. An important role for the alpha 1,3 fucosyltransferase, FucT-VII, in leukocyte adhesion to E-selectin.Blood. 1996; 88: 2125-2132PubMed Google Scholar). Selectin binding mediates many processes associated with cell-cell recognition and adhesion, including pathological processes such as leukocyte extravasation induced by chronic inflammation and distant organ metastasis by cancer cells. Thus, competitive inhibition of selectin binding has been of long-standing interest and has been recently reviewed (Ernst and Magnani, 2009Ernst B. Magnani J.L. From carbohydrate leads to glycomimetic drugs.Nat. Rev. Drug Discov. 2009; 8: 661-677Crossref PubMed Scopus (0) Google Scholar). Diseases of inflammatory extravasation and cancer cell metastasis (Azab et al., 2012Azab A.K. Quang P. Azab F. Pitsillides C. Thompson B. Chonghaile T. Patton J.T. Maiso P. Monrose V. Sacco A. et al.P-selectin glycoprotein ligand regulates the interaction of multiple myeloma cells with the bone marrow microenvironment.Blood. 2012; 119: 1468-1478Crossref PubMed Scopus (0) Google Scholar, Chien et al., 2013Chien S. Haq S.U. Pawlus M. Moon R.T. Estey E.H. Appelbaum F.R. Othus M. Magnani J.L. Adhesion of acute myeloid leukemia blasts to E-selectin in the vascular niche enhances their survival by mechanisms such as Wnt activation.Blood. 2013; 122: 61Crossref PubMed Scopus (0) Google Scholar, Okeley et al., 2013Okeley N.M. Alley S.C. Anderson M.E. Boursalian T.E. Burke P.J. Emmerton K.M. Jeffrey S.C. Klussman K. Law C.-L. Sussman D. et al.Development of orally active inhibitors of protein and cellular fucosylation.Proc. Natl. Acad. Sci. USA. 2013; 110: 5404-5409Crossref PubMed Scopus (65) Google Scholar), as well as sickle cell disease (Belcher et al., 2015Belcher J.D. Chen C. Nguyen J. Abdulla F. Nguyen P. Nguyen M. Okeley N.M. Benjamin D.R. Senter P.D. Vercellotti G.M. The fucosylation inhibitor, 2-fluorofucose, inhibits vaso-occlusion, leukocyte- endothelium interactions and NF-ÄB activation in transgenic sickle mice.PLoS One. 2015; 10: e0117772Crossref PubMed Scopus (0) Google Scholar, Chang et al., 2010Chang J. Patton J.T. Sarkar A. Ernst B. Magnani J.L. Frenette P.S. GMI-1070, a novel pan-selectin antagonist, reverses acute vascular occlusions in sickle cell mice.Blood. 2010; 116: 1779-1786Crossref PubMed Scopus (131) Google Scholar, Telen et al., 2015Telen M.J. Wun T. McCavit T.L. De Castro L.M. Krishnamurti L. Lanzkron S. Hsu L.L. Smith W.R. Rhee S. Magnani J.L. et al.Randomized phase 2 study of GMI-1070 in SCD: reduction in time to resolution of vaso-occlusive events and decreased opioid use.Blood. 2015; 125: 2656-2664Crossref PubMed Scopus (86) Google Scholar), have been treated by competitive inhibition of selectin binding. Following this initial success additional benefit has been leveraged in inhibition of adhesion-associated cell signaling and regulation. GMI-1070 and GMI-1271 are two fucose-containing competitive selectin inhibitors. These examples provide important insights into fucose biology and also validation of the strategy of fucose inhibition for treating diseases in the clinic. Competitive selectin inhibitors are usually carbohydrate analogs that are able to bind in the receptor site of the selectin protein, displacing the endogenous ligand. One of the most advanced examples is an intravenously administered pan-selectin inhibitor, GMI-1070, that has completed several clinical trials (Telen et al., 2015Telen M.J. Wun T. McCavit T.L. De Castro L.M. Krishnamurti L. Lanzkron S. Hsu L.L. Smith W.R. Rhee S. Magnani J.L. et al.Randomized phase 2 study of GMI-1070 in SCD: reduction in time to resolution of vaso-occlusive events and decreased opioid use.Blood. 2015; 125: 2656-2664Crossref PubMed Scopus (86) Google Scholar). Figure 2A shows the structures of GMI-1070, E-selectin inhibitor GMI-1271, and sialyl-Lewisx and sialyl-Lewisy, the endogenous ligands. The fucose and galactose residues appear in all structures as does the carboxylate of sialic acid and either an amide or an alkyl group in place of GlcNAc acetamide. These features are important in selectin binding as shown in Figures 2B and 2C for sialyl-Lewisx bound to E-selectin (PDB: 4CSY) (Preston et al., 2016Preston R.C. Binder F.P.C. Sager C.P. Ernst B. Jakob R.P. Maier T. E-selectin ligand complexes adopt an extended high-affinity conformation.J. Mol. Cell Biol. 2016; 8: 62-72Crossref PubMed Scopus (12) Google Scholar). The fucose residue (in yellow) is a particular recognition element, binding to calcium (blue) and forming beneficial electrostatic interactions with adjacent acidic residues deep within the binding pocket, and is critical to binding. The additional lipophilic substituents of GMI-1070 and GMI-1271 may form additional contacts with the receptor. The corresponding des-fuco glycan is not recognized. The naphthalene trisulfonate group of GMI-1070 likely interacts with serum albumin in order to extend the circulating half-life, while the polyethylene glycol of GMI-1271 may improve solubility and half-life. Competitive selectin inhibitors have been shown to have benefits in patients and in animal models of disease. (A) Competitive selectin inhibitors GMI-1070 and GMI-1271 compared with sialyl-Lewisx and sialyl-Lewisa terminal glycans. (B) Sialyl-Lewisx (SLex) terminal glycan (maize, fucose in yellow) co-crystallized with E-selectin (green ribbon) and calcium (blue sphere) (Preston et al., 2016Preston R.C. Binder F.P.C. Sager C.P. Ernst B. Jakob R.P. Maier T. E-selectin ligand complexes adopt an extended high-affinity conformation.J. Mol. Cell Biol. 2016; 8: 62-72Crossref PubMed Scopus (12) Google Scholar). The surface represents lipophilicity: purple areas are more polar areas of the binding pocket. The surface was calculated using Molecular Operating Environment (MOE), 2015.10, Chemical Computing Group. Rendering was by PyMOL, Schrodinger, LLC. (C) Terminal glycan structure of SLex. Sickle cell disease is highly dependent on cell adhesion. Polymorphonuclear neutrophils (PMNs) can capture sickle red blood cells (sRBCs) in the circulation. E-selectin on endothelia interacts with its ligand, E-selectin ligand-1, inducing polarized, activated αMβ2 integrin clusters at the leading edge of PMNs and thus captures sRBCs, leading to destructive and painful vaso-occlusion (Hidalgo et al., 2009Hidalgo A. Chang J. Jang J.E. Peired A.J. Chiang E.Y. Frenette P.S. Heterotypic interactions enabled by polarized neutrophil microdomains mediate thromboinflammatory injury.Nat. Med. 2009; 15: 384-391Crossref PubMed Scopus (187) Google Scholar). Therefore, disruption of E-selectin engagement by using selectin inhibitors may represent a valuable approach in sickle cell disease. Indeed, GMI-1070 has shown promise in the clinic in treating vaso-occlusive crisis in this disease. It was found that GMI-1070 predominantly inhibited E-selectin-mediated adhesion and dramatically inhibited sRBC-leukocyte interactions, leading to improved microcirculatory blood flow and improved survival (Chang et al., 2010Chang J. Patton J.T. Sarkar A. Ernst B. Magnani J.L. Frenette P.S. GMI-1070, a novel pan-selectin antagonist, reverses acute vascular occlusions in sickle cell mice.Blood. 2010; 116: 1779-1786Crossref PubMed Scopus (131) Google Scholar). In addition to this, a phase II clinical study has demonstrated that GMI-1070 treatment results in reduced time to resolve vaso-occlusive crises, reduced length of hospital stays, and reduced opioid use for pain management (Telen et al., 2015Telen M.J. Wun T. McCavit T.L. De Castro L.M. Krishnamurti L. Lanzkron S. Hsu L.L. Smith W.R. Rhee S. Magnani J.L. et al.Randomized phase 2 study of GMI-1070 in SCD: reduction in time to resolution of vaso-occlusive events and decreased opioid use.Blood. 2015; 125: 2656-2664Crossref PubMed Scopus (86) Google Scholar). Phase III studies on GMI-1070 in the treatment of vaso-occlusive crisis are now in recruitment (ClinicalTrials.gov identifiers, NCT02187003 and NCT02433158). Activation of cell signaling pathways is often secondary to selectin-mediated adhesion. Inhibition of pro-survival signaling within selectin-binding cells has also been demonstrated for GMI-1070. Multiple myeloma (MM) 1s cells treated with P-selectin or co-cultured with human umbilical vein endothelial cells (HUVECs) showed increased phosphorylation of pro-survival FAK, Src, cofilin, AKT, and GSK3α/β, signaling that was inhibited by GMI-1070 in a dose-dependent manner. In SCID mice in vivo, co-dosing with GMI-1070 and bortezomib significantly reduced MM tumors (Azab et al., 2012Azab A.K. Quang P. Azab F. Pitsillides C. Thompson B. Chonghaile T. Patton J.T. Maiso P. Monrose V. Sacco A. et al.P-selectin glycoprotein ligand regulates the interaction of multiple myeloma cells with the bone marrow microenvironment.Blood. 2012; 119: 1468-1478Crossref PubMed Scopus (0) Google Scholar). In a separate study, adhesion and stroma-induced proliferation and drug resistance to chemotherapy of MM cells was reduced by GMI-1271. GMI-1271 and lenalidomide delayed MM xenograft tumor growth by 64% compared with 35% for lenalidomide alone (Muz et al., 2017Muz B. Bazai H.Y. Sekula A. Fogler W.E. Smith T. Magnani J.L. Azab A.K. Abstract 5005: inhibition of E-selectin or E-selectin together with CXCR4 resensitizes multiple myeloma to treatment.Cancer Res. 2017; 77: 5005Crossref Google Scholar). Results similar to those for MM were observed in acute myeloid leukemia (AML) blasts treated with the specific E-selectin competitive inhibitor GMI-1271. Primary AML blasts from patients were found to upregulate several pro-survival pathways including Wnt signaling (2- to 3-fold) on binding to E-selectin-coated plates. GMI-1271 reduced Wnt upregulation and overcame adhesion-mediated chemotherapy resistance in these cells in vitro. GMI-1271 also reduced the leukemia burden in primary AML-engrafted NODscid IL2Rgc−/− mice in combination with chemotherapy (Chien et al., 2013Chien S. Haq S.U. Pawlus M. Moon R.T. Estey E.H. Appelbaum F.R. Othus M. Magnani J.L. Adhesion of acute myeloid leukemia blasts to E-selectin in the vascular niche enhances their survival by mechanisms such as Wnt activation.Blood. 2013; 122: 61Crossref PubMed Scopus (0) Google Scholar). GMI-1271 is in clinical trials in combination with chemotherapy for AML, showing statistically significant initial results in sensitizing cancer cells to chemotherapy and improving patient tolerance of therapy (ClinicalTrials.gov identifiers, NCT02306291 and NCT02811822) (DeAngelo et al., 2017DeAngelo D.J. Jonas B.A. Becker P.S. O'Dwyer M. Advani A.S. Marlton P. Magnani J. Thackray H.M. Liesveld J. GMI-1271, a novel E-selectin antagonist, combined with induction chemotherapy in elderly patients with untreated AML.J. Clin. Oncol. 2017; 35: 2560Crossref Google Scholar). These benefits were correlated to E-selectin expression level. Intensive high-dose chemotherapy or radiation can result in life-threatening neutropenia and mucositis. The oncolytic benefit of chemotherapy must be balanced with the resistance of normal tissues to the treatment. In mouse models deletion of E-selectin can increase the resistance of normal tissues to chemotherapy (Winkler et al., 2012Winkler I.G. Barbier V. Nowlan B. Jacobsen R.N. Forristal C.E. Patton J.T. Magnani J.L. Levesque J.-P. Vascular niche E-selectin regulates hematopoietic stem cell dormancy, self renewal and chemoresistance.Nat. Med. 2012; 18: 1651-1657Crossref PubMed Scopus (184) Google Scholar). E-selectin knockout mice (sele−/−) were found to have markedly reduced turnover of hematopoietic stem cells (HSCs). In the absence of signaling from E-selectin, HSCs in these mice remain in G0 phase quiescence in the perivascular bone marrow microenvironment and are non-reactive with antimetabolic or antiproliferative chemotherapy. After injection with the antimetabolite 5-fluorouracil (5-FU), 2.6-fold more HSCs survived in mouse femurs and after four injections of 5-FU given every 2 weeks, almost 8-fold more HSCs survived in sele−/− mice compared with wild-type (WT) mice. The sele−/− mice recovered a minimum threshold of blood leukocytes after ∼19 days versus 28 days for WT mice, and had a significant improvement in overall survival (Winkler et al., 2012Winkler I.G. Barbier V. Nowlan B. Jacobsen R.N. Forristal C.E. Patton J.T. Magnani J.L. Levesque J.-P. Vascular niche E-selectin regulates hematopoietic stem cell dormancy, self renewal and chemoresistance.Nat. Med. 2012; 18: 1651-1657Crossref PubMed Scopus (184) Google Scholar). Similar to the result in sele−/− mice, the pan-selectin inhibitor GMI-1070 administered for 18–25 days prior to chemotherapy in WT mice improved HSC survival and blood leukocyte recovery (Winkler et al., 2012Winkler I.G. Barbier V. Nowlan B. Jacobsen R.N. Forristal C.E. Patton J.T. Magnani J.L. Levesque J.-P. Vascular niche E-selectin regulates hematopoietic stem cell dormancy, self renewal and chemoresistance.Nat. Med. 2012; 18: 1651-1657Crossref PubMed Scopus (184) Google Scholar). sele−/− mice were also reported to have reduced therapy-induced weight loss that was ascribed to an almost complete lack of therapy-induced intestinal mucositis. Chemotherapy or radiation was found to induce a 10-fold upregulation of E-selectin in intestinal epithelium of WT mice that results in a wave of secondary inflammation as inflammatory cells are recruited to the mucosa, leading to therapy-induced mucositis. Macrophage migration to damaged intestines was completely abolished in sele−/− mice following chemotherapy or radiation. Similarly, GMI-1271, an E-selectin competitive inhibitor, when given to WT mice for 5 days following antimetabolic chemotherapy with gemcitabine, enhanced neutrophil recovery and protected the mice from weight loss and mucositis (Barbier et al., 2013Barbier V. Nutt H.L. Hasnain S.Z. Levesque J.-P. Magnani J.L. McGuckin M.A. Administration of E-selectin antagonist GMI-1271 improves survival after high-dose chemotherapy by alleviating mucositis and accelerating neutrophil recovery.Blood. 2013; 122: 2266Google Scholar). Interestingly, a phase I clinical trial of GMI-1271 in combination with filgrastim, the established neutropenia treatment, has recently been completed (ClinicalTrials.gov identifier, NCT02703051). Where competitive selectin inhibitors block selectin interactions with glycan, metabolic fucosylation inhibitors reduce the amount of fucosylated glycan. Fucose is added to glycan by FUTs that require GDP-fucose as a substrate. GDP-fucose can be generated either by the de novo pathway ultimately from glucose or by the salvage pathway that utilizes fucose recovered from lysosomal degradation of fucosylated glycans or from an extracellular origin (Figure 3A) (Becker and Lowe, 2003Becker D.J. Lowe J.B. Fucose: biosynthesis and biological function in mammals.Glycobiology. 2003; 13: 41R-53RCrossref PubMed Scopus (515) Google Scholar). The de novo pathway is highly conserved across species and accounts for most mammalian GDP-fucose. GDP-mannose 4,6-dehydratase (GMD) regulates the first committed step in the biosynthesis of GDP-fucose and is subject to potent feedback inhibition by GDP-fucose. The salvage pathway, on the other hand, can process fucose directly and is regulated by fucose kinase and GDP-fucose pyrophosphorylase (GFPP), with fucose-1-phosphate as the metabolic intermediate. The salvage pathway has also been leveraged to rescue genetic defects in the de novo pathway, for example, in the rare disorder leukocyte adhesion deficiency type II (Thiel and Koerner, 2013Thiel C. Koerner C. Therapies and therapeutic approaches in congenital disorders of glycosylation.Glycoconj. J. 2013; 30: 77-84Crossref PubMed Scopus (7) Google Scholar), and to deliver small-molecule fucose analogs into the cell. (A) The de novo and salvage GDP-fucose biosynthetic pathways. PMI, phosphomannose isomerase; PMM, phosphomannomutase; GMD, GDP-mannose 4,6-dehydratase; GFT, GDP-fucose transporter; FUT8, α(1,6)-fucosyltransferase; GFPP, GDP-fucose pyrophosphorylase. (B) Metabolic inhibitors of GDP-fucose. Through careful design, 2-deoxy-2-fluorofucose (2FF), peracetylated 6-alkynyl-fucose (6-Alk-Fuc) (Okeley et al., 2013Okeley N.M. Alley S.C. Anderson M.E. Boursalian T" @default.
• W2794128825 created "2018-03-29" @default.
• W2794128825 creator A5005580006 @default.
• W2794128825 creator A5006554324 @default.
• W2794128825 creator A5016419350 @default.
• W2794128825 creator A5089728692 @default.
• W2794128825 date "2018-05-01" @default.
• W2794128825 modified "2023-10-16" @default.
• W2794128825 title "Unmasking Fucosylation: from Cell Adhesion to Immune System Regulation and Diseases" @default.
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