The 3′ <i>IgH</i> Locus Control Region Is Sufficient to Deregulate a c-<i>myc</i> Transgene and Promote Mature B Cell Malignancies with a Predominant Burkitt-Like Phenotype

Truffinet, Véronique; Pinaud, Eric; Cogné, Nadine; Petit, Barbara; Guglielmi, Laurence; Cogné, Michel; Denizot, Yves

doi:10.4049/jimmunol.179.9.6033

Cited by 60 publications

(59 citation statements)

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“…In conclusion, the 3 0 RR is considered as a major lymphoma oncogene deregulator, [3][4][5] and its deletion has no effect on immune and inflammatory responses in the pristane mouse model. It is, thus, tempting to speculate that the 3 0 RR might be considered as a potential suitable target for anti-lymphoma pharmacological therapy without significant impact on the normal immune and inflammatory networks.…”

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confidence: 90%

“…Cyclin D1 and Bcl 0 RR in mature B-cell lymphomagenesis has been done by transgenic animal models. c-myc-3 0 RR transgenics developed Burkitt lymphoma-like proliferation, 3 and the knock-in of a 3 0 RR cassette upstream of the endogenous c-myc gene induced Bcell lymphomas. 4 Interestingly the phenotype of lymphoproliferations induced by the c-myc-3 0 RR transgene is affected by the presence of associated mutations in key cell cycle dependent genes such as p53 or Cdk4.…”

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confidence: 99%

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3′RR targeting in lymphomagenesis: a promising strategy?

Saintamand¹,

Saad

Denizot

2015

Cell Cycle

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confidence: 90%

mentioning

confidence: 99%

3′RR targeting in lymphomagenesis: a promising strategy?

Saintamand¹,

Saad

Denizot

2015

Cell Cycle

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“…2B). c-myc-3 0 RR transgenics developed Burkitt lymphoma-like proliferation within a few months [26] and similarly, the knock-in of a 3 0 RR cassette upstream of the endogenous c-myc gene induced B-cell lymphomas [27]. Interestingly, the phenotype of lymphoproliferation induced by the c-myc-3 0 RR transgene varied with the genetic background.…”

Section: C-myc 3 0 Rr and Lymphomagenesismentioning

confidence: 98%

“…Interestingly, the phenotype of lymphoproliferation induced by the c-myc-3 0 RR transgene varied with the genetic background. C57Bl/6 animals developed Burkitt-like lymphoma [26], while no lymphoproliferation occurred when the c-myc-3 0 RR transgene was bred in a Balb/c background (known to harbor a polymorphism of p16 Ink4a ) [28]. p16 Ink4a is an inhibitor of cyclin-dependent kinase (Cdk)-4, a regulatory protein implicated in the first steps of cell cycle entry.…”

Section: C-myc 3 0 Rr and Lymphomagenesismentioning

confidence: 99%

The IgH 3′ regulatory region and its implication in lymphomagenesis

et al. 2010

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The 3 0 regulatory region (3 0 RR) located downstream of the IgH gene is the master element that controls class switch recombination and sustains high-level transcription at the plasma-cell stage. This latter role suggests that the 3 0 RR may be involved in oncogene deregulation during the frequent IgH translocation events associated with B-cell malignancies. A convincing demonstration of the essential contribution of 3 0 RR in lymphomagenesis has been provided by transgenic animal models. The mouse 3 0 RR shares a strong structural homology with the regulatory regions located downstream of each human Ca gene. Mouse models exploring the role of the 3 0 RR in B-cell physiology and in malignancies should provide useful indications about the pathophysiology of human cell lymphocyte proliferation.Key words: B cells . Cellular proliferation . Oncology IntroductionDuring precursor B-cell differentiation, genes encoding heavy (H) and light chains of an Ig molecule are somatically assembled from germline DNA. This process, named V(D)J recombination, occurs in the bone marrow prior to antigenic challenge. In germinal centers during the antigen-dependent stages, variable (V) regions become the target of somatic hypermutation (SHM) in activated B cells allowing the generation of high-affinity Ig. In mature B cells, class switch recombination (CSR) deletes the constant (C) m region and replaces it with a downstream C H gene. This enables B cells to express various Ig isotypes but still retain antigen specificity. Once activated, B cells differentiate into Ig-secreting plasma cells. During B-cell development all these events (V(D)J recombination, SHM, CSR, Ig synthesis) are coupled with transcriptional accessibility of the IgH loci. IgH transcription is controlled by the functional interactions of multiple promoters, enhancers and insulators spread among the 2.5 megabases of the locus. Among them, the upstream Em enhancer and the 3 0 regulatory region (3 0 RR) stand out as major players. Chromosomal translocations linking oncogenes to these elements are often implicated as the cause of B-cell malignancies. In this brief review of relevant knock-out and transgenic mouse models, we underline how the physiological functions of the IgH 3 0 RR might translate into a critical role in oncogene deregulation during lymphomagenesis.From the El cis-activating element to the 3 0 RR Thirty years ago, Em was the first transcriptional enhancer discovered upstream of the m gene (Fig. 1A) [1][2][3]. Em deletion in mice confirmed its role in controlling access to the locus prior to D-J recombination, but, moreover, showed its dispensability for CSR and SHM [4]. Eventually, several more transcriptional enhancers were identified at the 3 0 end of the locus. hs1,2 was identified 12.5-kb downstream of the mouse Ca (Fig. 1A) 3306Mini-Review differentiation stages, while hs4 is active during the pre-B-cell stage and throughout B-cell development (Fig. 1A) [8,9]. The modest activity of each of the 3 0 RR elements, however, contributes to a synergic...

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“…The lymphomas generated in the original Eµ-Myc transgenic mice (the first model for MYCinduced cancer) do not reproduce BL well, 18,19 but additional transgenic mouse cell lines have been generated that better reproduce BL. These models for BL include models of mice carrying a single copy of the 240-kb IgH/c-Myc translocation region, 31 mice carrying the murine Myc cDNA inserted in the IgH locus in a site that correspond to the human t(8;14) translocation break, 32 mice with MYC linked to the 3′ IgH locus control region (3′ LCR), 33 or mice with combined MYC overexpression and constitutive activation of the PI3K. …”

Section: Burkitt Lymphomamentioning

confidence: 99%

MYC as therapeutic target in leukemia and lymphoma

Cortiguera¹,

Batlle-López²,

Albajar³

et al. 2015

BLCTT

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MYC is a transcription factor that is involved in the expression of many genes. Deregulated MYC is found in about half of human tumors, being more prevalent in hematological neoplasms. Deregulation mechanisms include chromosomal translocation (particularly in lymphoma), amplification, and hyperactivation of MYC transcription. Here we review MYC involvement in the major types of leukemia and lymphoma. MYC rearrangements appear in all Burkitt lymphomas and are common in other lymphoma types, whereas in acute lymphoblastic leukemia, acute myeloid leukemia, lymphoproliferative, and myeloproferative diseases, they are less frequent. However, MYC overexpression is present in all types of hematological malignancies and often correlates with a worse prognosis. Data in leukemia-derived cells and in animal models of lymphomagenesis and leukemogenesis suggest that MYC would be a good therapeutic target. Several MYC-directed therapies have been assayed in preclinical settings and even in clinical trials. First, peptides and small molecules that interrupt the MYC-MAX interaction impair MYCmediated tumorogenesis in several mouse models of solid tumors, although not yet in lymphoma and leukemia models. Second, there are a number of small molecules inhibiting the interaction of MYC-MAX heterodimers with DNA, still in the preclinical research phase. Third, inhibitors of MYC expression via the inhibition of BRD4 (a reader of acetylated histones) have been shown to control the growth of MYC-transformed leukemia and lymphoma cells and are being used in clinic trials. Finally, we review a number of promising MYC-mediated synthetic lethal approaches that are under study and have been tested in hematopoietic neoplasms.

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The 3′ IgH Locus Control Region Is Sufficient to Deregulate a c-myc Transgene and Promote Mature B Cell Malignancies with a Predominant Burkitt-Like Phenotype

Cited by 60 publications

References 34 publications

3′RR targeting in lymphomagenesis: a promising strategy?

3′RR targeting in lymphomagenesis: a promising strategy?

The IgH 3′ regulatory region and its implication in lymphomagenesis

MYC as therapeutic target in leukemia and lymphoma

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