Abstract
T(14;18) chromosomal translocation is assumed to result from illegitimate rearrangement between the BCL2 proto-oncogene and the IGH locus during the DH to JH joining phase of V(D)J recombination in early B cells. Analysis of the breakpoint junctions suggests that translocation derives from the fusion between normal V(D)J recombination intermediates at the IGH locus and non-V(D)J-mediated broken-ends at the BCL2 locus. So far, BCL2 broken-ends have only been observed fused to coding-ends, raising questions concerning the molecular constraints of the illegitimate joining process. Using a combination of genome walking and long-range PCR assays, we describe in this report that in 4.5% (2/44) of the t(14;18), one of the BCL2 broken-ends is fused to a signal-end. The formation of these JHRSS/BCL2 junctions provides direct evidence that BCL2 broken-ends are capable of joining to both products of V(D)J recombination, suggesting their presence in the RAG-mediated post-cleavage complex. In addition, junctions generated by this alternative end-joining do not involve deletion of the chromosome 14 intervening sequences generally lost in the standard translocation, providing a unique opportunity to investigate the rearrangement status of this region in the translocated IGH allele. In both cases, a DJH rearrangement could be detected 5′ of the JH-RSS/BCL2 junction. These findings, together with the previously reported bias towards the most external DH and JH segments in standard breakpoints, strongly suggest that t(14;18) preferentially occurs during an attempted secondary DH to JH rearrangement. This unusual and restricted window of differentiation opens intriguing questions concerning the etiology of the translocation.
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Acknowledgements
We are grateful to Ann J Feeney and Susanna M Lewis for comments on the manuscript. This work was supported by a grant for the Interdisciplinary Cooperation Project (ICP) from the University of Vienna, and a grant from the Fonds zur Foerderung der Wissenschaftlichen Forschung (FWF P-13984GEN).
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Marculescu, R., Le, T., Böcskör, S. et al. Alternative end-joining in follicular lymphomas’ t(14;18) translocation. Leukemia 16, 120–126 (2002). https://doi.org/10.1038/sj.leu.2402324
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DOI: https://doi.org/10.1038/sj.leu.2402324