Fig. 7.
Potential pathway to breakage-fusion-bridge (BFB) in AP145. Shown is a model representing potential molecular events that would result in the chromosomal aberrations observed in AP145 (Left). Recombination-activating gene 1/2 (RAG)-induced double-strand breaks (DSBs) left unrepaired at immunoglobin heavy chain (IgH) are replicated after progression in S phase. Both broken JH segments then insert into non-IgH sequence in a fashion highly analogous to other NHEJ/p53 pro-B cell tumors. However, because of a potential translocation bias, the broken JH ends preferentially insert around N-myc rather than c-myc in AP tumors. Based on the translocation breakpoint and cytogenetic analysis of tumor AP145, we propose that, after replication, both broken JH ends have invaded around N-myc on a single sister chromatid, generating a dicentric chromosome with internal copies of IgH (red) and N-myc (green) and IgH replacing N-myc near the centromere on one end. Resolution of this dicentric intermediate could then occur through a BFB cycle similar to what has been described for other NHEJ/p53 tumors (1-3). Consistent with this model, by FISH we observe a single copy of IgH at a centromeric position and coamplification of IgH and N-myc, capped by sequence from a third unrelated chromosome (Inset). This model also accounts for the undisturbed copy of chromosome 12 observed in these tumors.1. Gladdy, R. A., Taylor, M. D., Williams, C. J., Grandal, I., Karaskova, J., Squire, J. A., Rutka, J. T., Guidos, C. J. & Danska, J. S. (2003) Cancer Cell 3, 37-50.
2. Zhu, C., Mills, K. D., Ferguson, D. O., Lee, C., Manis, J., Fleming, J., Gao, Y., Morton, C. C. & Alt, F. W. (2002) Cell 109, 811-821.
3. Difilippantonio, M. J., Petersen, S., Chen, H. T., Johnson, R., Jasin, M., Kanaar, R., Ried, T. & Nussenzweig, A. (2002) J. Exp. Med. 196, 469-480.