title: Stereotypical chronic lymphocytic leukemia B-cell receptors recognize survival promoting antigens on stromal cells.
abstract: Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Survival of CLL cells depends on their close contact with stromal cells in lymphatic tissues, bone marrow and blood. This microenvironmental regulation of CLL cell survival involves the stromal secretion of chemo- and cytokines as well as the expression of adhesion molecules. Since CLL survival may also be driven by antigenic stimulation through the B-cell antigen receptor (BCR), we explored the hypothesis that these processes may be linked to each other. We tested if stromal cells could serve as an antigen reservoir for CLL cells, thus promoting CLL cell survival by stimulation through the BCR. As a proof of principle, we found that two CLL BCRs with a common stereotyped heavy chain complementarity-determining region 3 (previously characterized as "subset 1") recognize antigens highly expressed in stromal cells--vimentin and calreticulin. Both antigens are well-documented targets of autoantibodies in autoimmune disorders. We demonstrated that vimentin is displayed on the surface of viable stromal cells and that it is present and bound by the stereotyped CLL BCR in CLL-stroma co-culture supernatant. Blocking the vimentin antigen by recombinant soluble CLL BCR under CLL-stromal cell co-culture conditions reduces stroma-mediated anti-apoptotic effects by 20-45%. We therefore conclude that CLL BCR stimulation by stroma-derived antigens can contribute to the protective effect that the stroma exerts on CLL cells. This finding sheds a new light on the understanding of the pathobiology of this so far mostly incurable disease.
authors.affiliation: Department of Oncology and Hematology, Hubertus Wald Tumorzentrum/University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Mascha
authors.initials: M
authors.lastname: Binder
authors.forename: Barbara
authors.initials: B
authors.lastname: Léchenne
authors.forename: Ramesh
authors.initials: R
authors.lastname: Ummanni
authors.forename: Christan
authors.initials: C
authors.lastname: Scharf
authors.forename: Stefan
authors.initials: S
authors.lastname: Balabanov
authors.forename: Maria
authors.initials: M
authors.lastname: Trusch
authors.forename: Hartmut
authors.initials: H
authors.lastname: Schlüter
authors.forename: Ingke
authors.initials: I
authors.lastname: Braren
authors.forename: Edzard
authors.initials: E
authors.lastname: Spillner
authors.forename: Martin
authors.initials: M
authors.lastname: Trepel
mesh_terms: D000941:Antigens / Q000737:chemistry; D037282:Calreticulin / Q000737:chemistry; D022801:Complementarity Determining Regions / Q000235:genetics*; D015180:Electrophoresis, Gel, Two-Dimensional / Q000379:methods; D006367:HeLa Cells; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008856:Microscopy, Fluorescence / Q000379:methods; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods; D017154:Stromal Cells / Q000276:immunology; D014746:Vimentin / Q000737:chemistry
chemical_list: D000941:Antigens; D037282:Calreticulin; D022801:Complementarity Determining Regions; D007074:Immunoglobulin G; D011947:Receptors, Antigen, B-Cell; D011994:Recombinant Proteins; D014746:Vimentin