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Review
. 2010:106:93-133.
doi: 10.1016/S0065-2776(10)06004-9.

The role of mechanistic factors in promoting chromosomal translocations found in lymphoid and other cancers

Yu Zhang  1 , Monica Gostissa, Dominic G Hildebrand, Michael S Becker, Cristian Boboila, Roberto Chiarle, Susanna Lewis, Frederick W Alt
Affiliations
Review

The role of mechanistic factors in promoting chromosomal translocations found in lymphoid and other cancers

Yu Zhang et al. Adv Immunol. 2010.

Abstract

Recurrent chromosomal abnormalities, especially chromosomal translocations, are strongly associated with certain subtypes of leukemia, lymphoma and solid tumors. The appearance of particular translocations or associated genomic alterations can be important indicators of disease prognosis, and in some cases, certain translocations may indicate appropriate therapy protocols. To date, most of our knowledge about chromosomal translocations has derived from characterization of the highly selected recurrent translocations found in certain cancers. Until recently, mechanisms that promote or suppress chromosomal translocations, in particular, those responsible for their initiation, have not been addressed. For translocations to occur, two distinct chromosomal loci must be broken, brought together (synapsed) and joined. Here, we discuss recent findings on processes and pathways that influence the initiation of chromosomal translocations, including the generation fo DNA double strand breaks (DSBs) by general factors or in the context of the Lymphocyte-specific V(D)J and IgH class-switch recombination processes. We also discuss the role of spatial proximity of DSBs in the interphase nucleus with respect to how DSBs on different chromosomes are justaposed for joining. In addition, we discuss the DNA DSB response and its role in recognizing and tethering chromosomal DSBs to prevent translocations, as well as potential roles of the classical and alternative DSB end-joining pathways in suppressing or promoting translocations. Finally, we discuss the potential roles of long range regulatory elements, such as the 3'IgH enhancer complex, in promoting the expression of certain translocations that are frequent in lymphomas and, thereby, contributing to their frequent appearance in tumors.

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Figures

FIGURE 4.1
FIGURE 4.1
DNA rearrangement events in the IgH locus during B cell development. (See Text for details.)
FIGURE 4.2
FIGURE 4.2
Classic nonhomologous end joining in V(D)J recombination and general double-strand break repair. (Adapted from Dudley et al., 2005). (See text for details.)
FIGURE 4.3
FIGURE 4.3
Formation of recurrent reciprocal chromosomal translocations in tumors. First, two DSBs occur at two nonhomologous chromosomes. Then the four broken ends, after escape from normal DSB repair, are synapsed and ligated to form reciprocal chromosomal translocations. Finally, recurrent translocations in tumors are generally thought to arise spontaneously as very low-frequency events that are strongly selected at the cellular level via their contributions to oncogenesis.
FIGURE 4.4
FIGURE 4.4
The “contact-first” and “breakage-first” models for chromosomal translocation. (See text for details).
FIGURE 4.5
FIGURE 4.5
Chromosomal translocations involving aberrant V(D)J recombination and CSR. Left: aberrant V(D)J recombination between RSS in the IgH locus and cryptic RSS in a different chromosome. Middle: Formation of reciprocal translocations between RAG-generated and non-RAG-generated DSBs. In both these cases, the iEμ and IgH3′RR are both linked to c-myc and can potentially contribute to its over-expression (dotted arrows). Right: Formation of reciprocal translocations between AID-generated breaks at the IgH and c-Myc loci; only the IgH3′RR is present in this configuration and it has been shown to enhance c-myc expression (solid arrow). (see text for further details.)
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