Mutated VH genes and preferential VH3-21 use define new subsets of mantle cell lymphoma.
Mantle cell lymphoma (MCL) is believed to originate from a naive B cell. However, we recently demonstrated that a subset of MCL displayed mutated V(H) genes. We also reported restricted use of certain V(H) genes. To assess the prognostic impact of these new findings, we performed V(H) gene analysis of 110 patients, revealing that 18 (16%) patients had mutated and 92 (84%) patients had unmutated V(H) genes. Because the mutation rate was low in the mutated group (2.2%-6.7%), further investigation of the germline V(H) gene in T cells from 5 patients with mutated V(H) genes was carried out; results showed that the unrearranged V(H) gene was identical to the published sequence. These data confirm that the base pair substitutions within the rearranged V(H) genes represent hypermutations, and indicate germinal center exposure. However, V(H) gene mutation status did not correlate with prognosis because there was no difference in clinical outcome between the unmutated and mutated groups. The most frequently used V(H) genes were V(H)3-21 (21 patients) and V(H)4-34 (19 patients). A novel finding was that V(H)3-21(+) MCL almost exclusively expressed lambda light chains and displayed highly restricted use of the V(lambda)3-19 gene. V(H)3-21(+) patients had longer median survival than the remaining patients (53 vs 34 months; P =.03), but they tended to be younger at diagnosis. The combined use of V(H)3-21/V(lambda)3-19 suggests a possible role for antigen(s) in the pathogenesis of these tumors and indicates that V(H)3-21(+) patients constitute a new MCL entity.
Walsh
Sarah H
SH
Department of Genetics and Pathology, Uppsala University, Sweden.
Thorsélius
Mia
M
Johnson
Anna
A
Söderberg
Ola
O
Jerkeman
Mats
M
Björck
Erik
E
Eriksson
Inger
I
Thunberg
Ulf
U
Landgren
Ola
O
Ehinger
Mats
M
Löfvenberg
Eva
E
Wallman
Kristina
K
Enblad
Gunilla
G
Sander
Birgitta
B
Porwit-MacDonald
Anna
A
Dictor
Michael
M
Olofsson
Tor
T
Sundström
Christer
C
Roos
Göran
G
Rosenquist
Richard
R
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017931:DNA Primers; D005260:Female; D005803:Genes, Immunoglobulin; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007147:Immunoglobulin Light Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D020522:Lymphoma, Mantle-Cell / Q000145:classification / Q000235:genetics* / Q000276:immunology* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D012189:Retrospective Studies; D016019:Survival Analysis; D013997:Time Factors
D017931:DNA Primers; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D007135:Immunoglobulin Variable Region