Utilization of Ig heavy chain variable, diversity, and joining gene segments in children with B-lineage acute lymphoblastic leukemia: implications for the mechanisms of VDJ recombination and for pathogenesis.
Sequence analysis of the immunoglobulin heavy chain genes (IgH) has demonstrated preferential usage of specific variable (V), diversity (D), and joining (J) genes at different stages of B-cell development and in B-cell malignancies, and this has provided insight into B-cell maturation and selection. Knowledge of the association between rearrangement patterns based on updated databases and clinical characteristics of pediatric acute lymphoblastic leukemia (ALL) is limited. We analyzed 381 IgH sequences identified at presentation in 317 children with B-lineage ALL and assessed the V(H)D(H)J(H) gene utilization profiles. The D(H)J(H)-proximal V(H) segments and the D(H)2 gene family were significantly overrepresented. Only 21% of V(H)-J(H) joinings were potentially productive, a finding associated with a trend toward an increased risk of relapse. These results suggest that physical location at the V(H) locus is involved in preferential usage of D(H)J(H)-proximal V(H) segments whereas D(H) and J(H) segment usage is governed by position-independent molecular mechanisms. Molecular pathophysiology appears relevant to clinical outcome in patients who have only productive rearrangements, and specific rearrangement patterns are associated with differences in the tumor biology of childhood ALL.
Li
Aihong
A
Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
Rue
Montse
M
Zhou
Jianbiao
J
Wang
Hongjun
H
Goldwasser
Meredith A
MA
Neuberg
Donna
D
Dalton
Virginia
V
Zuckerman
David
D
Lyons
Cheryl
C
Silverman
Lewis B
LB
Sallan
Stephen E
SE
Gribben
John G
JG
D000293:Adolescent; D001402:B-Lymphocytes / Q000276:immunology; D001483:Base Sequence; D002051:Burkitt Lymphoma / Q000235:genetics / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D005260:Female; D015321:Gene Rearrangement / Q000235:genetics; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007133:Immunoglobulin Joining Region / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D007223:Infant; D008297:Male; D016133:Polymerase Chain Reaction; D014178:Translocation, Genetic; D045567:VDJ Recombinases / Q000235:genetics
D007143:Immunoglobulin Heavy Chains; D007133:Immunoglobulin Joining Region; D007135:Immunoglobulin Variable Region; D045567:VDJ Recombinases