Heterogeneous breakpoints on the immunoglobulin genes are involved in fusion with the 5' region of BCL2 in B-cell tumors.
The 5' flanking region of the BCL2 gene (5'-BCL2) is a breakpoint cluster of rearrangements with immunoglobulin genes (IGs). In contrast to t(14;18)(q32;q21) affecting the 3' region of BCL2, 5'-BCL2 can fuse to not only the heavy chain gene (IGH), but also two light chain gene (IGL) loci. We report here cloning and sequencing of a total of eleven 5'-BCL2 / IGs junctional areas of B-cell tumors, which were amplified by long-distance polymerase chain reaction-based assays. The breakpoints on 5'-BCL2 were distributed from 378 to 2312 bp upstream of the translational initiation site and, reflecting the alteration of regulatory sequences of BCL2, 5'-BCL2 / IGs-positive cells showed markedly higher levels of BCL2 expression than those of t(14;18)-positive cells. In contrast, the breakpoints on the IGs were variable. Two 5'-BCL2 / IGH and two 5'-BCL2 / IGLkappa junctions occurred 5' of the joining (J) segments, suggesting operation of an erroneous variable (V) / diversity (D) / J and V / J rearrangement mechanism. However, two other 5'-BCL2 / IGH junctions affected switch regions, and the kappa-deleting element, which is located 24 kb downstream of the constant region of IGLkappa, followed the 5'-BCL2 in another case. One 5'-BCL2 / IGLkappa and two 5'-BCL2 / IGLlambda junctions involved intronic regions where the normal recombination process does not occur. In the remaining one case, the 5'-BCL2 fused 3' of a Vlambda gene that was upstream of another Vlambda / Jlambda complex carrying a non-producing configuration, indicating that the receptor editing mechanism was likely involved in this rearrangement. Our study revealed heterogeneous anatomy of the 5'-BCL2 / IGs fusion gene leading to transcriptional activation of BCL2, and suggested that the mechanisms underlying the formation of this particular oncogene / IGs recombination are not identical to those of t(14;18).
Yonetani
N
N
First Division, Department of Internal Medicine, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
Ueda
C
C
Akasaka
T
T
Nishikori
M
M
Uchiyama
T
T
Ohno
H
H
D001483:Base Sequence; D019457:Chromosome Breakage; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics* / Q000648:ultrastructure; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics* / Q000648:ultrastructure; D004254:DNA Nucleotidyltransferases / Q000378:metabolism; D005091:Exons / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005803:Genes, Immunoglobulin; D019254:Genes, bcl-2; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007145:Immunoglobulin kappa-Chains / Q000235:genetics; D007146:Immunoglobulin lambda-Chains / Q000235:genetics; D007438:Introns / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D016393:Lymphoma, B-Cell / Q000235:genetics*; D008224:Lymphoma, Follicular / Q000235:genetics; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics; D016400:Lymphoma, Large-Cell, Immunoblastic / Q000235:genetics; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D016133:Polymerase Chain Reaction; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D014178:Translocation, Genetic / Q000235:genetics*; D045567:VDJ Recombinases
D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains; D007146:Immunoglobulin lambda-Chains; D015514:Oncogene Proteins, Fusion; D004254:DNA Nucleotidyltransferases; D045567:VDJ Recombinases