Subsets with restricted immunoglobulin gene rearrangement features indicate a role for antigen selection in the development of chronic lymphocytic leukemia.
We recently identified a chronic lymphocytic leukemia (CLL) subgroup using the immunoglobulin variable heavy-chain (V(H)) gene V(H)3-21 with almost identical heavy-chain complementarity determining region 3s (HCDR3s) and preferential variable light-chain (V(L)) gene usage, suggesting recognition of a common antigen epitope in this subset. To further explore the B-cell receptors (BCRs) in CLL, we characterized 407 V(H) rearrangements amplified from 346 CLLs regarding V(H), diversity (D), and joining (J(H)) gene usage and performed multiple alignment of the HCDR3 sequences. These analyses revealed 3 small subsets (2 V(H)1-69 groups, 7 cases; and 1 V(H)1-2 group, 5 cases) with highly restricted HCDR3 features including identical V(H)/D/J(H) usage, HCDR3 lengths, and shared N-sequences, in addition to the V(H)3-21 group (22 cases). Furthermore, another 3 groups (9 V(H)1-3(+) cases, 3 V(H)1-18(+) cases, and 5 V(H)4-39(+) cases) had essentially identical V(H)/D/J(H) use and similar HCDR3 lengths but less conserved N-regions. Analysis in all 6 of these subgroups showed restriction in V(L) gene use, whereas no association between V(H) and V(L) usage was found in cases without HCDR3 similarities. Altogether, structurally similar HCDR3s associated with preferential V(L) gene usage implies selection of BCRs, especially in subsets showing high HCDR3 similarities, thus pointing to restricted antigen recognition sites and possibly involvement of specific antigens in CLL development.
Tobin
Gerard
G
Dept of Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden.
Thunberg
Ulf
U
Karlsson
Karin
K
Murray
Fiona
F
Laurell
Anna
A
Willander
Kerstin
K
Enblad
Gunilla
G
Merup
Mats
M
Vilpo
Juhani
J
Juliusson
Gunnar
G
Sundström
Christer
C
Söderberg
Ola
O
Roos
Göran
G
Rosenquist
Richard
R
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D016175:B-Lymphocyte Subsets / Q000145:classification / Q000276:immunology / Q000473:pathology*; D022801:Complementarity Determining Regions / Q000235:genetics; D018985:Epitopes, B-Lymphocyte / Q000276:immunology*; D005260:Female; D015322:Gene Rearrangement, B-Lymphocyte / Q000276:immunology*; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain / Q000235:genetics / Q000276:immunology; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain / Q000235:genetics / Q000276:immunology; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000209:etiology / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology; D016415:Sequence Alignment
D022801:Complementarity Determining Regions; D018985:Epitopes, B-Lymphocyte; D011947:Receptors, Antigen, B-Cell