Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors.
To better understand the stage(s) of differentiation reached by B-type chronic lymphocytic leukemia (B-CLL) cells and to gain insight into the potential role of antigenic stimulation in the development and diversification of these cells, we analyzed the rearranged VH genes expressed by 83 B-CLL cells (64 IgM+ and 19 non-IgM+). Our results confirm and extend the observations of a bias in the use of certain VH, D, and JH genes among B-CLL cells. In addition, they indicate that the VH genes of approximately 50% of the IgM+ B-CLL cells and approximately 75% of the non-IgM+ B-CLL cells can exhibit somatic mutations. The presence of mutation varies according to the VH family expressed by the B-CLL cell (VH3 expressers displaying more mutation than VH1 and VH4 expressers). In addition, the extent of mutation can be sizeable with approximately 32% of the IgM+ cases and approximately 68% of the non-IgM+ cases differing by > 5% from the most similar germline gene. Approximately 20% of the mutated VH genes display replacement mutations in a pattern consistent with antigen selection. However, CDR3 characteristics (D and JH gene use and association and HCDR3 length, composition, and charge) suggest that selection for distinct B cell receptors (BCR) occurs in many more B-CLL cells. Based on these data, we suggest three prototypic BCR, representing the VH genes most frequently encountered in our study. These data suggest that many B-CLL cells have been previously stimulated, placing them in the "experienced" or "memory" CD5(+) B cell subset.
Fais
F
F
Department of Medicine, North Shore University Hospital and New York University School of Medicine, Manhasset, New York 11030, USA.
Ghiotto
F
F
Hashimoto
S
S
Sellars
B
B
Valetto
A
A
Allen
S L
SL
Schulman
P
P
Vinciguerra
V P
VP
Rai
K
K
Rassenti
L Z
LZ
Kipps
T J
TJ
Dighiero
G
G
Schroeder
H W
HW
Ferrarini
M
M
Chiorazzi
N
N
D000595:Amino Acid Sequence; D016175:B-Lymphocyte Subsets / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D001665:Binding Sites / Q000235:genetics; D018956:CD5 Antigens; D018076:DNA, Complementary / Q000235:genetics; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D006801:Humans; D007075:Immunoglobulin M / Q000096:biosynthesis; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology; D008969:Molecular Sequence Data; D009154:Mutation; D016364:Reading Frames; D011947:Receptors, Antigen, B-Cell / Q000235:genetics*; D017422:Sequence Analysis, DNA
D018956:CD5 Antigens; D018076:DNA, Complementary; D007075:Immunoglobulin M; D011947:Receptors, Antigen, B-Cell