Mouse Models of c-myc Deregulation Driven by IgH Locus Enhancers as Models of B-Cell Lymphomagenesis

Abstract

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.

Targeting miR-21 with NL101 blocks c-Myc/Mxd1 loop and inhibits the growth of B cell lymphoma

“…The transcription factor c-Myc is frequently dysregulated in hematological malignancies, especially in a large proportion of aggressive B cell lymphomas such as Burkitt lymphoma (BL) and diffuse large B cell lymphoma (DLBCL). The transgenic and knock-in mouse models in c-Myc driven by immunoglobulin heavy chain (IgH) locus enhancer highlights the critical role of c-Myc dysregulation in the development of B cell lymphoma 9 , 10 . The t(8;14) chromosomal translocation involving c-Myc rearrangement with IgH enhancer is considered as the cytogenetic hallmark of BL.…”

Enhancing B-Cell Malignancies—On Repurposing Enhancer Activity towards Cancer

“…Since Eµ and 3 RR are important regulators of the IGH locus activity throughout the B-cell lifetime, the intuitive questions to ask are: if and how can they be implicated in expression of translocated oncogenes? Mouse models of chromosomal translocations, juxtaposing oncogenes with Eµ and/or 3 RR allowed to build our current understanding of their engagement in B-cell malignancies [66,[189][190][191]. Three main study approaches can be distinguished: (1) regulation by Eµ; (2) regulation by 3 RR and (3) regulation by both Eµ and 3 RR, the most resembling endogenous conditions.…”

“…When choosing the mice model, main window of activity of each enhancer should also be kept in mind. Lymphomas developed in mice with an oncogene under regulation by Eµ only represent immature B-cell stage, while stimulation by 3 RR-only results in mature B-cell malignancies [189,192]. Animal models are important not only because they allow to understand the mechanisms driving oncogene expression and malignant transformation, but also provide an in vivo system for testing therapeutic approaches [193].…”

“…Up to date, several mouse models with IGH translocations have been established (Table 2). Eµ-myc mice have been so far the most widely used model [199], reviewed recently in more details by Ferrad et al [189]. It employs a construct in which Eµ enhancer is placed 5 to exon 1 of c-Myc.…”

“…Several knock-in models placing c-Myc under control of 3 RR enhancers have been developed. Those include: IgH-3 E-myc knock-in mice, iMycCα, iMycCµ and the use of "minimal 3 RR" (also reviewed in [189,190]). The first approach utilizes introduction of murine 3 RR DNase I hypersensitive sites into the endogenous c-Myc locus [202].…”