title: Burkitt lymphoma expresses oncofetal chondroitin sulfate without being a reservoir for placental malaria sequestration.
abstract: Burkitt lymphoma (BL) is a malignant disease, which is frequently found in areas with holoendemic Plasmodium falciparum malaria. We have previously found that the VAR2CSA protein is present on malaria-infected erythrocytes and facilitates a highly specific binding to the placenta. ofCS is absent in other non-malignant tissues and thus VAR2CSA generally facilitates parasite sequestration and accumulation in pregnant women. In this study, we show that the specific receptor for VAR2CSA, the oncofetal chondroitin sulfate (ofCS), is likewise present in BL tissue and cell lines. We therefore explored whether ofCS in BL could act as anchor site for VAR2CSA-expressing infected erythrocytes. In contrast to the placenta, we found no evidence of in vivo sequestering of infected erythrocytes in the BL tissue. Furthermore, we found VAR2CSA-specific antibody titers in children with endemic BL to be lower than in control children from the same malaria endemic region. The abundant presence of ofCS in BL tissue and the absence of ofCS in non-malignant tissue encouraged us to examine whether recombinant VAR2CSA could be used to target BL. We confirmed the binding of VAR2CSA to BL-derived cells and showed that a VAR2CSA drug conjugate efficiently killed the BL-derived cell lines in vitro. These results identify ofCS as a novel therapeutic BL target and highlight how VAR2CSA could be used as a tool for the discovery of novel approaches for directing BL therapy.
authors.affiliation: Centre for Medical Parasitology at Department of Immunology and Microbiology, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Mette Ø
authors.initials: MØ
authors.lastname: Agerbaek
authors.affiliation: Centre for Medical Parasitology at Department of Immunology and Microbiology, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Marina A
authors.initials: MA
authors.lastname: Pereira
authors.affiliation: Centre for Medical Parasitology at Department of Immunology and Microbiology, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark.|Vancouver Prostate Centre, Vancouver, BC, V6H 3Z6, Canada.|Department of Urologic Sciences, University of British Columbia, Vancouver, BC, V6H 3Z6, Canada.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Clausen
authors.affiliation: Centre for Medical Parasitology at Department of Immunology and Microbiology, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Caroline
authors.initials: C
authors.lastname: Pehrson
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC, V6H 3Z6, Canada.|Department of Urologic Sciences, University of British Columbia, Vancouver, BC, V6H 3Z6, Canada.
authors.forename: Htoo Zarni
authors.initials: HZ
authors.lastname: Oo
authors.affiliation: Centre for Medical Parasitology at Department of Immunology and Microbiology, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Spliid
authors.affiliation: Zymeworks Inc, Vancouver, BC, V6H 3V9, Canada.
authors.forename: Jamie R
authors.initials: JR
authors.lastname: Rich
authors.affiliation: Zymeworks Inc, Vancouver, BC, V6H 3V9, Canada.
authors.forename: Vincent
authors.initials: V
authors.lastname: Fung
authors.affiliation: Noguchi Memorial Institute, Accra, Ghana.
authors.forename: Francis
authors.initials: F
authors.lastname: Nkrumah
authors.affiliation: Department of Child Health, Korle Bu University Teaching Hospital, Accra, Ghana.
authors.forename: Janet
authors.initials: J
authors.lastname: Neequaye
authors.affiliation: Institute of Health and Biotechnology, Queensland University of Technology, Brisbane, Australia.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Biggar
authors.affiliation: Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Reynolds
authors.affiliation: Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Tosato
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles.
authors.forename: Sheeja T
authors.initials: ST
authors.lastname: Pullarkat
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, Ohio.
authors.forename: Leona W
authors.initials: LW
authors.lastname: Ayers
authors.affiliation: Centre for Medical Parasitology at Department of Immunology and Microbiology, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Thor G
authors.initials: TG
authors.lastname: Theander
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC, V6H 3Z6, Canada.|Department of Urologic Sciences, University of British Columbia, Vancouver, BC, V6H 3Z6, Canada.
authors.forename: Mads
authors.initials: M
authors.lastname: Daugaard
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Kishor
authors.initials: K
authors.lastname: Bhatia
authors.affiliation: Centre for Medical Parasitology at Department of Immunology and Microbiology, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Morten A
authors.initials: MA
authors.lastname: Nielsen
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, Ohio.
authors.forename: Sam M
authors.initials: SM
authors.lastname: Mbulaiteye
authors.affiliation: Centre for Medical Parasitology at Department of Immunology and Microbiology, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Ali
authors.initials: A
authors.lastname: Salanti
mesh_terms: D000293:Adolescent; D000913:Antibodies, Protozoan / Q000097:blood; D000951:Antigens, Neoplasm / Q000378:metabolism*; D000953:Antigens, Protozoan / Q000276:immunology; D002051:Burkitt Lymphoma / Q000378:metabolism* / Q000469:parasitology; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D002809:Chondroitin Sulfates / Q000378:metabolism*; D004912:Erythrocytes / Q000469:parasitology; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D016778:Malaria, Falciparum / Q000150:complications / Q000378:metabolism*; D008297:Male; D010920:Placenta / Q000378:metabolism* / Q000469:parasitology*; D010963:Plasmodium falciparum / Q000276:immunology; D011247:Pregnancy; D011509:Proteoglycans / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D000913:Antibodies, Protozoan; D000951:Antigens, Neoplasm; D000953:Antigens, Protozoan; D007074:Immunoglobulin G; D011509:Proteoglycans; D011994:Recombinant Proteins; C512601:VAR2CSA protein, Plasmodium falciparum; C031192:oncofetal antigens; D002809:Chondroitin Sulfates
keywords: Burkitt lymphoma; CSA; Plasmodium falciparum; VAR2CSA; cancer; chondroitin sulfate A; chondroitin sulfate proteoglycan; malaria