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.
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.
Tobin
Gerard
G
Department of Genetics and Pathology, Uppsala University, Sweden.
Thunberg
Ulf
U
Johnson
Anna
A
Eriksson
Inger
I
Söderberg
Ola
O
Karlsson
Karin
K
Merup
Mats
M
Juliusson
Gunnar
G
Vilpo
Juhani
J
Enblad
Gunilla
G
Sundström
Christer
C
Roos
Göran
G
Rosenquist
Richard
R
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
D022801:Complementarity Determining Regions; D000939:Epitopes; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D007146:Immunoglobulin lambda-Chains