Eμ and 3′RR transcriptional enhancers of the IgH locus cooperate to promote c-myc–induced mature B-cell lymphomas

Ghazzaui, Nour; Issaoui, Hussein; Ferrad, Mélissa; Carrion, Claire; Cook-Moreau, Jeanne; Denizot, Yves; Boyer, François

doi:10.1182/bloodadvances.2019000845

Cited by 8 publications

(8 citation statements)

References 52 publications

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“…′ to C µ with E µ deletion (namely iMycC µ mice), thus modeling human sporadic BL, confirmed that 3'RR alone is sufficient to deregulate c-myc in the B-cell lineage and to induce B-cell lymphoma development (70). Taken altogether, these KI models carrying c-myc at the IgH locus are prone to B-cell lymphomas of various penetrance, kinetics, and fate as recently reported in a study comparing the three mouse models (71). The lymphoma signatures are also heterogeneous even comparing lymphomas from a specific KI, mirroring the genomic differences observed between the various subtypes of human mature B-cell lymphomas and those previously reported with the model of transgenic E µ -Myc mice.…”

Section: The Combination Of E µ and 3'rr Cis-transcriptional Enhancersupporting

confidence: 71%

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

et al. 2020

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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.

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Section: The Combination Of E µ and 3'rr Cis-transcriptional Enhancersupporting

confidence: 71%

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

et al. 2020

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“…Another model of c-Myc driven Burkitt's lymphoma is one driven solely by the 3' regulatory region of the IgH locus rather than the Eµ enhancer. This model results in the development of B-cell malignancies with a mature B-cell phenotype in contrast to the Eµ model wherein a pro-B phenotype is predominant (27,28).…”

Section: Need For the Development Of New Murine Models For B-cell Malignanciesmentioning

confidence: 97%

The Eµ-hnRNP K Murine Model of Lymphoma: Novel Insights into the Role of hnRNP K in B-Cell Malignancies

et al. 2021

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B-cell lymphomas are one of the most biologically and molecularly heterogeneous group of malignancies. The inherent complexity of this cancer subtype necessitates the development of appropriate animal model systems to characterize the disease with the ultimate objective of identifying effective therapies. In this article, we discuss a new driver of B-cell lymphomas – hnRNP K (heterogenous nuclear ribonucleoprotein K)—an RNA-binding protein. We introduce the Eµ-Hnrnpk mouse model, a murine model characterized by hnRNP K overexpression in B cells, which develops B-cell lymphomas with high penetrance. Molecular analysis of the disease developed in this model reveals an upregulation of the c-Myc oncogene via post-transcriptional and translational mechanisms underscoring the impact of non-genomic MYC activation in B-cell lymphomas. Finally, the transplantability of the disease developed in Eµ-Hnrnpk mice makes it a valuable pre-clinical platform for the assessment of novel therapeutics.

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“…Existing studies on Ig enhancer polymorphisms were done on a very small scale and there are conflicting conclusions about their potential role in diseases [ 119 , 120 ]. However, mutations in Ig heavy enhancer have been previously implicated in B-cell lymphomas [ 121 ]. The 3′ regulatory region and the switch regions of human and murine Ig loci have been shown to contain hotspots for oestrogen receptor binding [ 122 , 123 ].…”

Section: Enhancers and Their Role In Regulating Ig Expressionmentioning

confidence: 99%

Immunoglobulin germline gene variation and its impact on human disease

2021

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Immunoglobulins (Ig) play an important role in the immune system both when expressed as antigen receptors on the cell surface of B cells and as antibodies secreted into extracellular fluids. The advent of high-throughput sequencing methods has enabled the investigation of human Ig repertoires at unprecedented depth. This has led to the discovery of many previously unreported germline Ig alleles. Moreover, it is becoming clear that convergent and stereotypic antibody responses are common where different individuals recognise defined antigenic epitopes with the use of the same Ig V genes. Thus, germline V gene variation is increasingly being linked to the differential capacity of generating an effective immune response, which might lead to varying disease susceptibility. Here, we review recent evidence of how germline variation in Ig genes impacts the Ig repertoire and its subsequent effects on the adaptive immune response in vaccination, infection, and autoimmunity.

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Eμ and 3′RR transcriptional enhancers of the IgH locus cooperate to promote c-myc–induced mature B-cell lymphomas

Abstract: 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.

Cited by 8 publications

References 52 publications

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

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

The Eµ-hnRNP K Murine Model of Lymphoma: Novel Insights into the Role of hnRNP K in B-Cell Malignancies

Immunoglobulin germline gene variation and its impact on human disease

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