Distribution and features of unclustered CCND1 breakpoints and a model for CpG and WGCW breaks in IgH translocations. (A) A 400-kb segment of chromosome 11q13 (chr11:68 800 000-69 200 000 in NCBI Build 36) is shown. The MYEOV and CCND1 genes and MTC are shown for reference. CpG breakpoints are shown above the axis, and non-CpG breakpoints are shown below. Blue represents κ-restricted cases; red, λ-restricted cases; and ○, cases for which light chain restriction is unknown. (B) Our results implicate AID-initiated chromosomal breaks in the genesis of IgH-CCND1 translocations in MCL, IgH-MYC translocations in Burkitt lymphoma, and IgH-BCL6 translocations in follicular and diffuse large B-cell lymphomas (see supplemental Results). AID expression is highest in antigen-stimulated mature B cells undergoing somatic hypermutation and CSR but is expressed at lower levels in immature and transitional 1 (T1) B cells, and at even lower levels in pro-B and pre-B cells. RAG activity is associated with V(D)J recombination in pro-B cells during IgH rearrangement, in pre-B cells during light chain rearrangement, and in immature B cells during receptor editing. Lightning bolts indicate the stage at which each translocation is proposed to occur. Our model proposes that low levels of AID favor CpG breaks (blue font), whereas intermediate or high levels of AID favor WGCW breaks (red). The staggered cytosine bases on opposite strands of the CpG and WGCW motifs are highlighted to indicate the potential of this configuration to promote DSBs.