Chromosomal translocations linking various oncogenes to transcriptional enhancers of the immunoglobulin heavy chain (IgH) locus are often implicated as the cause of B-cell malignancies. Two major IgH transcriptional enhancers have been reported so far. The E µ enhancer located upstream of the C µ gene controls early events in B-cell maturation such as VDJ recombination. The 3' regulatory region (3'RR) located downstream from the C α gene controls late events in B-cell maturation such as IgH transcription, somatic hypermutation, and class switch recombination. Convincing demonstrations of the essential contributions of both E µ and 3'RR in B-cell lymphomagenesis have been provided by transgenic and knock-in animal models which bring the oncogene c-myc under E µ /3'RR transcriptional control. This short review summarizes the different mouse models so far available and their interests/limitations for progress in our understanding of human c-myc-induced B-cell lymphomagenesis.

Key Points Transcriptional cooperation between IgH Eμ and 3′RR enhancers is found during B-cell lymphomagenesis in IgH-c-myc mice. Transcriptome analysis reveals wide similarities between human and mouse Burkitt B-cell lymphomas.

After encountering antigen, B-cells undergo class switch recombination (CSR) that substitutes the constant (C) μ gene with C γ , C ε , or C α , thereby generating IgG, IgE, and IgA antibodies with new effector functions but the same antigenic specificity. 1 The DNA-editing enzyme activation-induced deaminase (AID) is required for CSR by targeting specific DNA switch (S) regions preceding the C region, except C δ. 2 S μ is the donor region, while S γ,ε,α are the acceptor regions. CSR is controlled in cis by the immunoglobulin heavy chain (IgH) 3'regulatory region (3'RR). 3 The 3'RR is essential to poise AID on the S acceptor region. During CSR IgH, intrachromosomal interactions (schematized in Fig. 1a) are found between the 3'RR and the intronic E μ enhancer. 1,4 Looping allows transcriptional binding activators to enhancers to facilitate CSR. However, CSR is only modestly influenced by E μ deletion. 5-7 During CSR, two different DNA repair pathways take place: the classical nonhomologous end joining (c-NHEJ) and the alternative end joining (A-EJ) pathways. The c-NHEJ pathway (which uses components such as 53BP1, Ku70, ku80, XRCC4, and ligase 4) is preferentially implicated for blunt and microhomology structure junctions and the A-EJ pathway (which uses components such as CtIP, MRN, PARP1, DNA Pol θ) favors junctions with large homology. 8,9 Data have reported that when an element of the DNA damage response pathway is defective, the molecular signature of CSR junctions is affected, suggesting that junctions are repaired through a different DNA repair pathway. 10 We recently reported a new computational tool (CSReport) for the automatic analysis of CSR junctions sequenced by high-throughput sequencing, 11 and used it to analyze the rare S μ-S δ junctions during IgD CSR, 12,13 S μ-S γ,α junctions in wild-type (wt) mice 14 and UNG-deficient mice. 15 Even if E μ-deficient mice exhibited a modest defect in IgH CSR, it is conceivable that its participation in CSR 3D loop interactions would be important for the DNA repair process. We used the CSReport and high-throughput sequencing to analyze the molecular signature of S μ-S γ3, S μ-S γ1 , and S μ-S α junctions in E μ-deficient mice to perform a more in depth search for a putative difference in their DNA repair pathways compared to those in wt mice. The mice were housed and the procedures were conducted in agreement with European Directive 2010/63/EU on animals used for scientific purposes applied in France as the « Décret n°2012-118 du 1 er février 2013 relatif à la protection des animaux utilisés à des fins scientifiques ». Accordingly, the present project (APAFiS≠13855) was authorized by the « Ministère de l'Education Nationale, de l'Enseignement