The c-MYC allele that is translocated into the IgH locus undergoes constitutive hypermutation in a Burkitt's lymphoma line

Bemark, Mats; Neuberger, Michael S.

doi:10.1038/sj.onc.1203686

Cited by 56 publications

(60 citation statements)

References 49 publications

(57 reference statements)

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“…Specifically, the V region accumulates many mutations in Ramos clones A.2 and A.5 ( Table 1) that have Ϸ25-fold higher levels of AID mRNA than Ramos clones C.1 and A.1 (8). Bcl-6 and the c-myc allele that has translocated into the switch region also have been shown to undergo SHM in B cell lines (20,21). To determine whether overexpression of AID in Ramos cells also activated mutation in these genes, bcl-6 and c-myc were sequenced from 2-month-old cultures of Ramos clones that overexpressed AID.…”

Section: Resultsmentioning

confidence: 99%

Somatic hypermutation of the AID transgene in B and non-B cells

Martín

Scharff

2002

Proc. Natl. Acad. Sci. U.S.A.

149

109

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Somatic hypermutation (SHM) of the Ig genes is required for affinity maturation of the humoral response to foreign antigens. Activation-induced cytidine deaminase (AID), which is specifically expressed in germinal center centroblasts, is indispensable for this process. Expression of AID is sufficient to activate SHM in hybridomas, non-B cells, and Escherichia coli, suggesting that it initiates the mutational process by deaminating DNA. However, the cisacting sequences that are responsible for targeting AID activity to the variable (V) region of Ig genes are unknown. Here we show that expression of AID in B cell lines (i.e., Burkitt's lymphoma Ramos and hybridoma P1-5) not only causes hypermutation of Ig sequences, but also of the AID transgene itself. Because it is possible that B cell-specific transacting factors bind to and recruit the ''mutator'' to the AID transgene, we tested whether the AID transgene can mutate in non-B cells. Indeed, we show that expression of AID in Chinese hamster ovary cells causes SHM of both the Ig and AID transgenes. These data suggest that high transcription rates alone may predispose any gene to mutation by AID but do not preclude that there are specific B cell factors that account for the extremely high rate of V mutation in vivo and its targeting to the V region.A ffinity maturation of the antibody response is mediated by somatic hypermutation (SHM) of the antibody genes with subsequent selection of B cell clones that produce higher affinity antibodies to the immunizing antigen. SHM causes point mutations and occasional deletions and insertions at very high rates of Ϸ10 Ϫ3 bp per generation and occurs during the centroblast stage of B cell differentiation. The mutations are restricted to the variable region (V region) that encodes the antibody binding site and to sequences that are Ϸ1.5 kb downstream from the Ig promoter. Some of these mutations increase the affinity of the antibody so that it can neutralize viruses and toxins and inactivate pathogenic organisms.Mice and humans with mutations in activation-induced cytidine deaminase (AID) have defects in SHM (1, 2), class-switch recombination (1), and gene conversion (3, 4). Based on the sequence similarity of AID to the RNA-editing enzyme APOBEC-1 (5), it was postulated that AID might function by editing a specific message that results in the production of an altered protein that subsequently causes mutation (6). However, the higher than expected number of transition mutations in V regions (7) raises the possibility that AID might be a DNAspecific cytidine deaminase that converts C to U nucleotides directly in the DNA of the V region. In fact, we recently showed that AID induced the P1-5 hybridoma to exclusively mutate G⅐C bp, and most of these mutations were transition mutations (8). With the finding that AID can induce SHM in non-B cells (9) and Escherichia coli (4), it is more likely that AID is a DNA-specific cytidine deaminase.The mechanism for targeting of SHM to the V region of Ig genes is not known. Interestingly, SHM h...

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Section: Resultsmentioning

confidence: 99%

Somatic hypermutation of the AID transgene in B and non-B cells

Martín

Scharff

2002

Proc. Natl. Acad. Sci. U.S.A.

149

109

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“…2A). Next, we used BJAB Burkitt's lymphoma cells, in which the c-IRF4 gene is intact but the c-Myc gene is translocated to the IgG promoter region (31). TRExBJAB cells expressing vector (pcDNA) or vIRF4 in a tetracycline-inducible manner were treated with or without Doxy and then subjected to RT-qPCR and immunoblot analyses (Fig.…”

Section: Resultsmentioning

confidence: 99%

Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 4 (vIRF4) Targets Expression of Cellular IRF4 and the Myc Gene To Facilitate Lytic Replication

Lee

Doğanay

Chung

et al. 2014

J Virol

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“…Further, in Burkitt's lymphoma the translocated CMYC gene shows somatic mutations (Rabbitts et al, 1983(Rabbitts et al, , 1984 in a manner analogous to mutations of V genes further suggesting that lymphoid chromosomal translocations involve natural genetic instability of Ig genes. Indeed some Burkitt's lymphoma cell lines have been identi®ed in which the process of somatic V gene or CMYC mutation can still be observed (Bemark and Neuberger, 2000;Sale and Neuberger, 1998). We conclude that chromosomal translocations into Ig/ TCR genes occur by mistakes of mechanisms evolved for diversi®cation of the immune system.…”

Section: Lymphoid Chromosomal Translocations Are Linked To Mechanismsmentioning

confidence: 99%

Chromosomal translocation master genes, mouse models and experimental therapeutics

Rabbitts

2001

Oncogene

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Molecular biologists have elucidated general principles about chromosomal translocations by cloning oncogenes or fusion genes at chromosomal translocation junctions. These genes invariably encode intracellular proteins and in acute cancers, often involve transcription and developmental regulators, which are master regulators of cell fate (e.g. LMO2 which is involved in acute leukaemia). Chromosomal translocations are usually associated with speci®c cell types. The reason for this close association is under investigation using mouse models. We are trying to emulate the cell-speci®c consequences of chromosomal translocations in mice using homologous recombination in embryonic stem cells to generate de novo chromosomal translocations or to mimic the consequence of these translocations. In addition, chromosomal translocation genes and their products are important targets for therapy. We have designed new therapeutic strategies which include antigen-speci®c recruitment of endogenous cellular pathways to a ect cellular viability and a novel structured form of antisense to ablate the function of fusion mRNAs. We will evaluate these procedures in the mouse models of chromosomal translocations and the long term aim is to perfect rapid procedures for characterizing patient-speci®c chromosomal translocations to tailor therapy to individual patients. Oncogene (2001) 20, 5763 ± 5777.

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The c-MYC allele that is translocated into the IgH locus undergoes constitutive hypermutation in a Burkitt's lymphoma line

Cited by 56 publications

References 49 publications

Somatic hypermutation of the AID transgene in B and non-B cells

Somatic hypermutation of the AID transgene in B and non-B cells

Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 4 (vIRF4) Targets Expression of Cellular IRF4 and the Myc Gene To Facilitate Lytic Replication

Chromosomal translocation master genes, mouse models and experimental therapeutics

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