Although chromosomal translocations that involve the immunoglobulin heavy chain (IgH) locus are a defining feature of B-cell malignancies, little is know about how these translocations occur or what the mechanisms are that guard against these potentially tumorigenic events. Almudena Ramiro, Mila Jankovic and colleagues have unravelled some of these mechanisms in their recent Nature paper.

The authors examined the function of activation-induced cytidine deaminase (AID) — an enzyme that is essential for the switching of immunoglobulin class (for example, from IgM to IgG or IgA) during B-cell activation — in the production of translocations between Myc and Igh in primary mouse B cells. AID has previously been shown to be essential for the accumulation of Myc–Igh translocations, but the mechanism involved is unclear. Ramiro et al. compared the numbers of translocations produced in Aid−/− cells with those occurring in Aid−/− cells that were infected with a retroviral construct containing Aid.

Activation of the B cells resulted in the accumulation of Myc–Igh translocations in the AID-overexpressing cells, but no effect was evident in the Aid−/− cells. Proteins involved in the non-homologous end-joining (NHEJ) pathway of DNA repair are known to be required for the resolution of the double-strand breaks within the immunoglobulin switch region, but the authors found that the NHEJ pathway was not needed for Myc–Igh translocations to occur.

Loss of the DNA-damage transducer ATM, which is required for immunoglobulin class switching, increased the frequency of Myc–Igh translocations in AID-expressing cells. Moreover, absence or haploinsufficiency of the tumour suppressor p53 — a downstream target of ATM — led to high levels of Myc–Igh translocations. Because the aberrant expression of MYC is known to activate the ARF–p53 tumour-suppressor pathway, the authors also looked for, and found, increased occurrences of Myc–Igh translocations in ARF-null B cells. Therefore, the authors conclude that ATM, p53 and ARF are part of the mechanism that detects and protects against the occurrence of Myc–Igh translocations. Despite the genomic instability induced by the loss of ATM, the authors found no evidence that genomic instability promotes the formation of Myc–Igh translocations.

The authors have proposed a model to account for their findings. Class switching requires the formation of AID-induced DNA double-strand breaks, and these are correctly repaired by the NHEJ system and a host of other proteins involved in the detection and repair of DNA double-strand breaks, including ATM but excluding p53. Lesions that are not resolved induce a p53 response through the activation of ATM. It is the cells that escape this response and make NHEJ-independent translocations that activate the ARF pathway, resulting once again in p53 activation. So, p53 mutation or loss is likely to contribute early on to the pathogenesis of lymphoma by facilitating AID-induced translocations.