title: The IGHV1-69/IGHJ3 recombinations of unmutated CLL are distinct from those of normal B cells.
abstract: IGHV1-69/51p1 is expressed by ∼ 30% of unmutated chronic lymphocytic leukemia (U-CLL) and combines with selected IGHD and IGHJ genes generating stereotypes if HCDR3 amino acid homology is > 60%. We had previously revealed stereotypic IGHV1-69/IGHJ6 rearrangements in normal naive B cells, thereby identifying potential counterparts of U-CLL. A different stereotypic IGHV1-69/IGHD3-16(RF2)/IGHJ3 rearrangement carrying the CAR(GGx)YD motif in the N1-region, recurrent in 6% IGHV1-69+ve CLL, is exceptionally sequence restricted, strongly suggestive of shared antigen recognition. We have now analyzed IGHV1-69/IGHJ3 rearrangements in circulating B cells of healthy individuals using several PCR-based approaches with IGHV1-69/IGHJ3 CLL sequences for reference. Stereotypes were found, but all were distinct from CLL. Remarkably, even a highly sensitive semi-nested PCR, specific for the CLL-expressed IGHV1-69/IGHD3-16(RF2)/IGHJ3 stereotype, failed to identify the CAR(GGx)YD sequence, although similar motifs were found. These highly specific B cells are not apparent in the accessible normal repertoire and may expand in response to rarely expressed antigens important in the pathogenesis of CLL.
authors.affiliation: Hematology, Department of Clinical Medicine and Immunological Sciences, University of Siena and Department of Oncology, Azienda Ospedaliera Universitaria Senese, Siena, Italy. f.forconi@soton.ac.uk
authors.forename: Francesco
authors.initials: F
authors.lastname: Forconi
authors.forename: Kathleen N
authors.initials: KN
authors.lastname: Potter
authors.forename: Elisa
authors.initials: E
authors.lastname: Sozzi
authors.forename: Isla
authors.initials: I
authors.lastname: Henderson
authors.forename: Emanuele
authors.initials: E
authors.lastname: Cencini
authors.forename: Davide
authors.initials: D
authors.lastname: Rossi
authors.forename: Riccardo
authors.initials: R
authors.lastname: Bomben
authors.forename: Valter
authors.initials: V
authors.lastname: Gattei
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.forename: Graham
authors.initials: G
authors.lastname: Packham
authors.forename: Freda K
authors.initials: FK
authors.lastname: Stevenson
mesh_terms: D000595:Amino Acid Sequence; D001402:B-Lymphocytes / Q000378:metabolism*; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain / Q000235:genetics*; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D016415:Sequence Alignment; D060152:V(D)J Recombination / Q000235:genetics*
chemical_list: D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region