Translocations involving the immunoglobulin heavy chain ( Igh ) locus and Myc are oncogenic, but the elements that are involved in activating the transcription of these fusion genes have not been resolved. Fred Alt, Monica Gostissa and colleagues have used mouse models to show that the Igh 3′ regulatory region (Igh3′ RR) can function over long distances to activate the transcription of translocated Myc.

B cells expand their receptor repertoire by rearrangements at the Igh locus using two mechanisms: V(D)J recombination in developing B cells and class switch recombination in mature B cells. These rearrangements are promoted by two elements, the intronic enhancer (iEμ) in V(D)J recombination and the Igh3′ RR in class switch recombination, and both of these sequences are oncogenic when fused to Myc in transgenic mouse models. However, iEμ is frequently deleted by Igh–Myc translocations, often leaving the translocated Myc gene more than 200 kb upstream of the Igh3′ RR. In these instances, is Igh3′ RR required for lymphomagenesis?

To address this question, Gostissa and colleagues deleted the Igh3′ RR from mouse models of B cell lymphoma. p53-deficient mice expressing loxP-flanked Xrcc4 alleles develop peripheral B cell lymphoma when Xrcc4 is inactivated using a Cre recombinase. The Igh–Myc translocations in these mice are initiated by class switch recombination, and the authors showed that inactivation of Igh3′ RR prevented the development of peripheral B cell lymphomas. The Igh–Myc fusions identified in these B cell lymphomas always involved the Igh locus with an intact Igh3′ RR. In addition, inactivation of Igh3′ RR in normal B cell progenitors did not affect the frequency of Igh–Myc translocations. Therefore, the authors conclude that Igh3′ RR is required for peripheral B cell Igh–Myc-induced lymphomagenesis owing to its capacity to activate translocated Myc genes over long distances. They also suggest that this regulatory element could be involved in pro-B cell tumours in which iEμ is inactivated. Consequently, targeting the Igh3′ RR is a potential treatment for certain types of B cell lymphoma.