title: Binding of CLL subset 4 B-cell receptor immunoglobulins to viable human memory B lymphocytes requires a distinctive IGKV somatic mutation.
abstract: Amino acid replacement mutations in certain CLL stereotyped B-cell receptor (BCR) immunoglobulins (IGs) at defined positions within antigen-binding sites strongly imply antigen selection. Prime examples of this are CLL subset 4 BCR IGs using IGHV4-34/IGHD5-18/IGHJ6 and IGKV2-30/IGKJ2 rearrangements. Conspicuously and unlike most CLL IGs, subset 4 IGs do not bind apoptotic cells. By testing the (auto)antigenic reactivities of subset 4 IGs toward viable lymphoid-lineage cells and specific autoantigens typically bound by IGHV4-34+IGs, we found IGs from both subset 4 and non-subset 4 IGHV4-34-expressing CLL cases bind naïve B cells. However, only subset 4 IGs react with memory B cells. Furthermore, subset 4 IGs do not bind DNA nor i or I carbohydrate antigens, common targets of IGHV4-34-utilizing antibodies in systemic lupus erythematosus and cold agglutinin disease, respectively. Notably, we found that subset 4 IG binding to memory B lymphocytes depends on an aspartic acid at position 66 of FR3 in the rearranged IGKV2-30 gene; this amino acid residue is acquired by somatic mutation. Our findings illustrate the importance of positive and negative selection criteria for structural elements in CLL IGs and suggest that autoantigens driving normal B cells to become subset 4 CLL cells differ from those driving IGHV4-34+B cells in other diseases.
authors.affiliation: Karches Center for Oncology Research, The Feinstein Institute for Medical Research, Manhasset, NY, 11030, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Catera
authors.affiliation: Karches Center for Oncology Research, The Feinstein Institute for Medical Research, Manhasset, NY, 11030, USA.|Hofstra Northwell School of Medicine, Hempstead, NY, 11549, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Glycosciences Laboratory, Imperial College London, Department of Medicine, Burlington Danes Building, Du Cane Road, London W12 0NN, UK.
authors.forename: Chao
authors.initials: C
authors.lastname: Gao
authors.affiliation: Karches Center for Oncology Research, The Feinstein Institute for Medical Research, Manhasset, NY, 11030, USA.
authors.forename: Xiao-Jie
authors.initials: XJ
authors.lastname: Yan
authors.affiliation: Karches Center for Oncology Research, The Feinstein Institute for Medical Research, Manhasset, NY, 11030, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Magli
authors.affiliation: Karches Center for Oncology Research, The Feinstein Institute for Medical Research, Manhasset, NY, 11030, USA.|Hofstra Northwell School of Medicine, Hempstead, NY, 11549, USA.|Department of Medicine, Hofstra Northwell School of Medicine, Hempstead, NY, 11549, USA.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Allen
authors.affiliation: Karches Center for Oncology Research, The Feinstein Institute for Medical Research, Manhasset, NY, 11030, USA.|Hofstra Northwell School of Medicine, Hempstead, NY, 11549, USA.|Department of Medicine, Hofstra Northwell School of Medicine, Hempstead, NY, 11549, USA.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Kolitz
authors.affiliation: Karches Center for Oncology Research, The Feinstein Institute for Medical Research, Manhasset, NY, 11030, USA.|Hofstra Northwell School of Medicine, Hempstead, NY, 11549, USA.|Department of Medicine, Hofstra Northwell School of Medicine, Hempstead, NY, 11549, USA.
authors.forename: Kanti R
authors.initials: KR
authors.lastname: Rai
authors.affiliation: Karches Center for Oncology Research, The Feinstein Institute for Medical Research, Manhasset, NY, 11030, USA.|Hofstra Northwell School of Medicine, Hempstead, NY, 11549, USA.|Department of Medicine, Hofstra Northwell School of Medicine, Hempstead, NY, 11549, USA.
authors.forename: Charles C
authors.initials: CC
authors.lastname: Chu
authors.affiliation: Glycosciences Laboratory, Imperial College London, Department of Medicine, Burlington Danes Building, Du Cane Road, London W12 0NN, UK.
authors.forename: Ten
authors.initials: T
authors.lastname: Feizi
authors.affiliation: Institute of Applied Biosciences, Centre for Research and Technology-Hellas, Thessaloniki, Greece.
authors.forename: Kostas
authors.initials: K
authors.lastname: Stamatopoulos
authors.affiliation: Karches Center for Oncology Research, The Feinstein Institute for Medical Research, Manhasset, NY, 11030, USA.|Hofstra Northwell School of Medicine, Hempstead, NY, 11549, USA.|Department of Medicine, Hofstra Northwell School of Medicine, Hempstead, NY, 11549, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Chiorazzi
keywords: CD10 antigen; VK mutation; chronic lymphocytic leukemia; memory B cells; stereotyped B-cell receptor