*2.1.3. V(D)J recombination, class switch recombination, and neoplastic transformation*

One evident deviation of the normal V(D)J recombination and CSR processes is the possibility of rearrangements between segments belonging to different genes. In fact, reciprocal chromosomal translocations are the most common recurrent genetic anomalies in lymphoid malignancies and the newly formed junctions generated in most human lymphoid translocations have the canonical features of NHEJ [15].

One paradigmatic example is follicular (FL), a lymphoid neoplasm characterized by the t(14;18)(q32;q21) translocation that juxtaposes the anti-apoptotic proto-oncogene BCL2 to the immunoglobulin heavy chain locus [16]. The functional result of this translocation is constitutive transcriptional upregulation of BCL2. Although this translocation is considered the founding event in FL pathogenesis, t(14;18)-positive B cells can be detected in many healthy individuals [17]. Therefore, this genetic event alone seems insufficient to cause lymphoma.

The t(11;14)(q13;q32) translocation, a hallmark of mantle cell lymphoma (MCL), results in the overexpression of cyclin D1 and also appears to be a V(D)J-mediated translocation [18]. As in FL, the sole constitutive overexpression of this cell cycle regulator is insufficient to explain malignant transformation.

Whereas the t(14;18) or t(11;14) translocations result from a mistake during V(D)J recombination, some translocations involve the IgH class switch regions in a failed CSR event. Translocations at the IgH class switch regions seem to depend on AID activity and commonly involve c-MYC and BCL-6 [19]. BCL6 is the most commonly rearranged gene in activated B cell (ABC) diffuse large B-cell lymphoma (DLBCL) and c-MYC rearrangements can be observed in Burkitt lymphoma (BL) and DLBCL.

BCL6 is a proto-oncogene encoding a transcriptional repressor expressed during B cell differentiation in germinal centers. A block in the normal downregulation of BCL6, through its translocation with more than 20 possible partner genes, might favor differentiation arrest, continuous cell proliferation, survival, and genetic instability [20]. BCL6 also suppresses the activity of the tumor suppressor gene TP53, which allows BCL6-expressing cells to escape apoptosis [21].

The c-MYC gene at 8q24 is involved in three translocations observed in DLBCL, most commonly t(8;14) (q24;q32), and less often t(2;8) (p12;q24) and t(8;22) (q24;q11) [21]. In the t(8;14) (q24;q32) translocation, also observed in BL, the gene segments from the IgH locus are joined with various regions around and within the c-MYC proto-oncogene [22]. As a result, IgH regulatory elements are misplaced upstream, of the c-MYC proto-oncogene [23].

Four recurrent translocations, t(1;14)(p22;q32), t(3;14)(p14.1;q32), t(11;18)(q21;q21), and t(14;18)(q32;q21), have been described in marginal zone B-cell lymphomas of MALT type. The two latter translocations involve the MALT1 gene. These translocations seem to occur as a result of illegitimate V(D)J-mediated recombination [22, 24].
