V(H) gene usage differs in germline and mutated B-cell chronic lymphocytic leukemia.
OBJECTIVE
Given the prognostic relevance that the identification of mutated and germline subgroups of chronic lymphocytic leukemia (CLL) has recently acquired we set out to analyze in depth individual VH gene usage rearrangements in patients with mutated and germline CLL.


METHODS
Using sequence analysis of FR1/JH polymerase chain reaction products, the VH immunoglobulin gene configuration was analyzed in 159 rearranged IgH alleles from 154 CLL patients. Having previously identified a spatial relationship between VH gene usage and JH proximity in patients with acute lymphocytic leukemia (ALL), we performed linear and Poisson regression analysis on patients with germline and mutated CLL against VH rearrangements from normal peripheral blood.


RESULTS
Sequence analysis showed that 102 patients (64%) had mutated sequences (>2% DNA base pair changes) while 57 (36%) had germline sequences. The germline CLL group showed JH proximal overusage similar to that reported in ALL patients, while the mutated CLL group showed a pattern comparable to that of the control group (peripheral blood rearranged VH sequences). The CDR3 region was statistically longer in the patients with germline CLL than in those with mutated CLL.


CONCLUSIONS
This study highlights differences in the VDJ profile in mutated and germline CLL, consistent with the suggestion that CLL comprises two subgroups. The interpretation of these differences is that the B-cell of CLL, particularly in the germline group, may derive from a pool that has been unable to follow or complete the normal pathway of B-cell differentiation.
Duke
Veronique M
VM
Department of Hematology, RFUCSM, United Kingdom.
Gandini
Domenica
D
Sherrington
Paul D
PD
Lin
Ke
K
Heelan
Bridget
B
Amlot
Peter
P
Mehta
Atul B
AB
Hoffbrand
A Victor
AV
Foroni
Letizia
L
D000483:Alleles; D001402:B-Lymphocytes / Q000737:chemistry; D002454:Cell Differentiation; D015331:Cohort Studies; D022801:Complementarity Determining Regions / Q000235:genetics; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D005803:Genes, Immunoglobulin; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007133:Immunoglobulin Joining Region / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000737:chemistry; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics
D022801:Complementarity Determining Regions; D004273:DNA, Neoplasm; D007143:Immunoglobulin Heavy Chains; D007133:Immunoglobulin Joining Region; D009363:Neoplasm Proteins