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B cell lymphomas represent 95% of all lymphomas diagnosed in the Western world and the majority of these arise from germinal center (GC) B cells (1). Recurrent chromosomal translocations involving Ig loci and proto-oncogenes are a hallmark of many types of B cell lymphoma (2). Three types of breakpoints can be identified in Ig loci. Translocation breakpoints adjacent to the DH or JH gene segments form secondary to V(D)J recombination, a process that occurs in early B cell development. Other translocations are located in rearranged V(D)J exons that have acquired mutations indicating that translocation is a byproduct of somatic hypermutation (SHM) which occurs in GC B cells. A third type of translocation is characterized by breakpoints in the Igh switch regions, a target for double strand DNA breaks (DSBs) during class switch recombination (CSR) that occurs in mature B cells, both inside and outside the GC. Thus, in B lymphocytes, V(D)J joining, CSR, and SHM create obligate single- or double-strand DNA breaks as intermediates for chromosomal translocations (3, 4).  Activation-induced deaminase (AID) is the enzyme that initiates CSR and SHM (5) by inducing the formation of DSBs in switch (S) regions and mutations in V gene exons (6–10). Studies indicate that non-Ig genes are mistargeted by AID (11, 12) and thereby acquire single and double strand DNA breaks at sites coincident with translocation breakpoints (1, 2). Mature B cells are particularly prone to chromosomal translocations that juxtapose Ig genes and proto-oncogenes, including c-myc [Burkitt’s lymphoma (BL)], Bcl-2 (follicular lymphoma), Bcl-6 (diffuse large cell lymphoma), and FGFR (multiple myeloma) and which are characteristic of human B cell malignancies (2). The mouse plasmacytoma (PCT) T(12;15)(Igh-myc) translocation, a direct counterpart of the human BL t(8;14)(q24;q32) translocation, occurs as a dynamic process in mature B cells undergoing CSR and is dependent on the expression of AID (13, 14). Hence, a direct mechanistic link between AID and chromosomal translocations focused to Ig genes has been established.  One of the most puzzling aspects of recurrent chromosomal translocations is that DSBs on two different chromosomes must come into close proximity frequently enough to facilitate the crossover. How do the broken ends located at distal sites in cis or on trans chromosomes come together? Consideration of oncogenic selection, sources of translocation prone DSBs associated with antigen receptor rearrangements in B and T lymphocytes, and the role of DSB persistence in translocations have been recently reviewed [(15, 16) and references therein]. Here we consider the proposition that the spatial organization of mammalian genomes is intrinsically linked to genome stability and modulates the frequency of chromosomal translocations.

Genomic Architecture may Influence Recurrent Chromosomal Translocation Frequency in the Igh Locus