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 o f rearrangements with immunoglobulin genes (IGs). In contrast to t(14;18)(q 32;q21) affecting the 3' region of BCL2, 5'-BCL2 can fuse to not only the h eavy 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 are as of B-cell tumors, which were amplified by long-distance polymerase chain reaction-based assays. The breakpoints on 5'-BCL2 were distributed from 37 8 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) -p ositive cells. In contrast, the breakpoints on the IGs were variable. Two 5 '-BCL2/IGH and two 5'-BCL2/IGL kappa 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 junctio ns affected switch regions, and the kappa -deleting element, which is locat ed 24 kb downstream of the constant region of IGL kappa followed the 5'-BCL 2 in another case. One 5'-BCL2/IGL kappa and two 5'-BCL2/IGL lambda junctio ns involved intronic regions where the normal recombination process does no t occur. In the remaining one case, the 5'-BCL2 fused 3' of a V lambda gene that was upstream of another V lambda /J lambda complex carrying a non-pro ducing configuration, indicating that the receptor editing mechanism was li kely involved in this rearrangement. Our study revealed heterogeneous anato my of the 5'-BCL2/ IGs fusion gene leading to transcriptional activation of BCL2, and suggested that the mechanisms underlying the formation of this p articular oncogene/IGs recombination are not identical to those of t(14;18) .