Chronic lymphocytic leukemia B cells can undergo somatic hypermutation and intraclonal immunoglobulin V(H)DJ(H) gene diversification.
Chronic lymphocytic leukemia (CLL) arises from the clonal expansion of a CD5(+) B lymphocyte that is thought not to undergo intraclonal diversification. Using V(H)DJ(H) cDNA single strand conformation polymorphism analyses, we detected intraclonal mobility variants in 11 of 18 CLL cases. cDNA sequence analyses indicated that these variants represented unique point-mutations (1-35/patient). In nine cases, these mutations were unique to individual submembers of the CLL clone, although in two cases they occurred in a large percentage of the clonal submembers and genealogical trees could be identified. The diversification process responsible for these changes led to single nucleotide changes that favored transitions over transversions, but did not target A nucleotides and did not have the replacement/silent nucleotide change characteristics of antigen-selected B cells. Intraclonal diversification did not correlate with the original mutational load of an individual CLL case in that diversification was as frequent in CLL cells with little or no somatic mutations as in those with considerable mutations. Finally, CLL B cells that did not exhibit intraclonal diversification in vivo could be induced to mutate their V(H)DJ(H) genes in vitro after stimulation. These data indicate that a somatic mutation mechanism remains functional in CLL cells and could play a role in the evolution of the clone.
Division of Molecular Immunology, Department of Pathology, Cornell University Weill Medical College, New York, NY 10021, USA.
Carmela
C
Gurrieri
Peter
P
McGuire
Hong
H
Zan
Xiao-Jie
XJ
Yan
Andrea
A
Cerutti
Emilia
E
Albesiano
Steven L
SL
Allen
Vincent
V
Vinciguerra
Kanti R
KR
Rai
Manlio
M
Ferrarini
Paolo
P
Casali
Nicholas
N
Chiorazzi
D000916:Antibody Diversity / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D019143:Evolution, Molecular; D005260:Female; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D006801:Humans; D066298:In Vitro Techniques; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology*; D008297:Male; D008969:Molecular Sequence Data; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational
D018076:DNA, Complementary; D004273:DNA, Neoplasm