title: Antisera induced by infusions of autologous Ad-CD154-leukemia B cells identify ROR1 as an oncofetal antigen and receptor for Wnt5a.
abstract: We examined the sera of six patients before and after i.v. infusions of autologous chronic lymphocytic leukemia (CLL) cells transduced ex vivo with an adenovirus encoding CD154 (Ad-CD154). Five patients made high-titer antibodies against adenovirus and three made IgG reactive with a leukemia-associated surface antigen, which we identified as ROR1. Anti-ROR1 antibodies were not detected in the sera of untreated patients. We generated anti-ROR1 mAbs and found they reacted specifically with the CLL cells of all patients, but not with nonleukemic leukocytes, a wide variety of normal adult tissues, or blood mononuclear cells, including CD5(+) B cells of healthy adults. ROR1 could bind Wnt5a, which induced activation of NF-kappaB when coexpressed with ROR1 in HEK293 cells and enhanced the survival of CLL cells in vitro, an effect that could be neutralized by posttreatment anti-ROR1 antisera. We conclude that patients with CLL can break immune tolerance to ROR1, which is an oncofetal surface antigen and survival-signaling receptor in this neoplastic disease.
authors.affiliation: Moores Cancer Center, and Chronic Lymphocytic Leukemia Research Consortium, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Fukuda
authors.forename: Liguang
authors.initials: L
authors.lastname: Chen
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Endo
authors.forename: Li
authors.initials: L
authors.lastname: Tang
authors.forename: Desheng
authors.initials: D
authors.lastname: Lu
authors.forename: Januario E
authors.initials: JE
authors.lastname: Castro
authors.forename: George F
authors.initials: GF
authors.lastname: Widhopf
authors.forename: Laura Z
authors.initials: LZ
authors.lastname: Rassenti
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Cantwell
authors.forename: Charles E
authors.initials: CE
authors.lastname: Prussak
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Carson
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
mesh_terms: D000256:Adenoviridae / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D001483:Base Sequence; D023201:CD40 Ligand / Q000276:immunology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D017931:DNA Primers; D018076:DNA, Complementary / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007106:Immune Sera / Q000276:immunology*; D015151:Immunoblotting; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D017422:Sequence Analysis, DNA; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000378:metabolism*; D000071818:Wnt-5a Protein
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D017931:DNA Primers; D018076:DNA, Complementary; D007106:Immune Sera; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C031192:oncofetal antigens; D023201:CD40 Ligand; C078716:ROR1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D057050:Receptor Tyrosine Kinase-like Orphan Receptors