title: Chronic lymphocytic leukemias utilizing the VH3-21 gene display highly restricted Vlambda2-14 gene use and homologous CDR3s: implicating recognition of a common antigen epitope.
abstract: The immunoglobulin variable heavy chain (IgVH) gene mutation status is an important prognostic factor in chronic lymphocytic leukemia (CLL), since cases with mutated VH genes show significantly longer survival than unmutated cases. Recently, we reported a preferential use of the VH3-21 gene in mutated CLL and showed that mutated VH3-21 cases had an inferior overall survival compared with other mutated CLL. In order to further characterize this subset, we performed VH gene analysis in 265 CLL cases and identified 31 VH3-21 cases (11.7%); 21 cases had mutated and 10 cases unmutated VH genes. Regardless of VH gene mutation status, a poor overall survival was found in the VH3-21 cases with a median survival of 83 months. These survival data confirm that VH3-21 cases do not fit into the general prognostic grouping of mutated and unmutated CLL. A large fraction of VH3-21 cases also demonstrated unique features with shorter lengths of the third complementarity determining region (CDR3) and CDR3s with highly homologous amino acid sequences. Furthermore, the VH3-21 cases showed a striking dominance of lambda light chain expression, and analysis of the Iglambda gene rearrangements revealed highly restricted use of the Vlambda2-14/Jlambda3 genes in the majority of cases. Taken together, our new findings strengthen the suggestion that VH3-21-using cases comprise a new CLL entity, irrespective of VH gene mutation status, and implicate that a common antigen epitope, perhaps of pathogenic significance, is recognized by the highly homologous VH3-21/Vlambda2-14 Ig molecules expressed in individual tumors.
authors.affiliation: Department of Genetics and Pathology, Uppsala University, Sweden.
authors.forename: Gerard
authors.initials: G
authors.lastname: Tobin
authors.forename: Ulf
authors.initials: U
authors.lastname: Thunberg
authors.forename: Anna
authors.initials: A
authors.lastname: Johnson
authors.forename: Inger
authors.initials: I
authors.lastname: Eriksson
authors.forename: Ola
authors.initials: O
authors.lastname: Söderberg
authors.forename: Karin
authors.initials: K
authors.lastname: Karlsson
authors.forename: Mats
authors.initials: M
authors.lastname: Merup
authors.forename: Gunnar
authors.initials: G
authors.lastname: Juliusson
authors.forename: Juhani
authors.initials: J
authors.lastname: Vilpo
authors.forename: Gunilla
authors.initials: G
authors.lastname: Enblad
authors.forename: Christer
authors.initials: C
authors.lastname: Sundström
authors.forename: Göran
authors.initials: G
authors.lastname: Roos
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
mesh_terms: D000595:Amino Acid Sequence; D022801:Complementarity Determining Regions / Q000737:chemistry* / Q000235:genetics; D017124:Conserved Sequence; D000939:Epitopes / Q000276:immunology*; D015321:Gene Rearrangement; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000737:chemistry / Q000235:genetics*; D007146:Immunoglobulin lambda-Chains / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology / Q000401:mortality; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D011379:Prognosis; D017422:Sequence Analysis, DNA; D017385:Sequence Homology; D015996:Survival Rate
chemical_list: D022801:Complementarity Determining Regions; D000939:Epitopes; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D007146:Immunoglobulin lambda-Chains