Role of genomic instability and p53 in AID-induced c-myc–Igh translocations

Ramiro, Almudena R.; Janković, Mila; Callén, Elsa; Difilippantonio, Simone; Chen, Hua-Tang; McBride, Kevin M.; Eisenreich, Thomas; Chen, Junjie; Dickins, Ross A.; Lowe, Scott W.; Nussenzweig, André; Nussenzweig, Michel C.

doi:10.1038/nature04495

Cited by 319 publications

(395 citation statements)

References 31 publications

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“…Our results combined with previous results (Ramiro et al, 2004(Ramiro et al, , 2006Franco et al, 2006b;Dorsett et al, 2007) suggest that the primary oncogenic role of AID is to induce c-myc/IgH translocations. Another possibility is that AID does not have an impact on lymphoma development when c-myc/IgH translocation events precede AID expression.…”

Section: Reduced Rag1 Expression In B Cells Does Not Impact C-myc Lymsupporting

confidence: 71%

“…AID is specifically expressed in germinal center B cells (Muramatsu et al, 2000) and initiates somatic hypermutation and class switch recombination in Ig genes by deaminating cytidines within Ig genes (reviewed in (Di Noia and Neuberger, 2007)). Numerous reports show that c-myc/IgH or bcl-2/IgH translocations are mediated by the RAG proteins (Korsmeyer, 1992;Raghavan et al, 2004) and by the AID enzyme (Ramiro et al, 2004(Ramiro et al, , 2006Franco et al, 2006b;Dorsett et al, 2007), and indeed, these enzymes have been found to mutate or cause DNA breaks outside of Ig genes (Korsmeyer, 1992;Shen et al, 1998;Muschen et al, 2000;Pasqualucci et al, 2001;Franco et al, 2006a) reinforcing the possibility that many other genes are susceptible to AID-and RAG-mediated mutations. Although RAG proteins and AID mediate chromosomal translocations, it has yet to be established whether these enzymes play additional roles in subsequent transformation events.…”

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confidence: 99%

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AID and RAG1 do not contribute to lymphomagenesis in Eμ c-myc transgenic mice

et al. 2008

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DNA breaks caused by recombination-activating gene 1 (RAG1) and activation-induced cytidine deaminase (AID) induce c-myc/immunoglobulin (Ig) heavy chain chromosomal translocations and thereby stimulate lymphomagenesis. However, constitutive expression of c-myc alone is not sufficient to induce lymphomas. Because RAG1 and AID activity occurs outside of Ig genes, we assessed whether these enzymes provide the secondary genetic lesions in El c-myc transgenic mice to promote lymphoma development. We found that the tumor incidence and tumor phenotype in El c-myc transgenic mice is similar in AID þ / þ , AID þ /À and AID À/À backgrounds in both specific pathogen-free and conventional animal facilities, indicating that AID does not contribute to lymphoma development in El c-myc transgenic mice. To examine the role of RAG proteins in El c-myc mice, we examined El c-myc transgenic mice that harbor the Ig-HEL heavy-and light-chain transgenes, and thus have reduced RAG expression in B cells. We found that tumor incidence was not affected by these Ig transgenes. However, we found that RAG1 À/À El c-myc mice exhibited accelerated tumor development compared to controls. This data combined with our finding that El c-myc mice lived longer in the conventional facility than in the specific pathogen-free facility suggest an immunemediated activity that suppresses lymphoma development.

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Section: Reduced Rag1 Expression In B Cells Does Not Impact C-myc Lymsupporting

confidence: 71%

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confidence: 99%

AID and RAG1 do not contribute to lymphomagenesis in Eμ c-myc transgenic mice

et al. 2008

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“…Fifth, Tp53 deficiency leads to or unmasks the oncogenic potential of RAG-dependent Igh/c-myc and Tcra/c-myc translocations and AID-initiated Igh/c-myc translocations in lymphocytes lacking histone H2AX Celeste et al, 2003a;Bassing et al, 2007). Sixth, Tp53 suppresses the frequency of nonmalignant B cells with AID-initiated Igh/c-myc translocations (Ramiro et al, 2006;Santos et al, 2010). Seventh, Tp53 À/À mice with inactivation of NHEJ in mature B cells succumb to tumors with oncogenic Igh/cmyc translocations arising through CSR errors, or clonal translocations involving aberrant Igk and Igl V(D)J recombination (Wang et al, 2008(Wang et al, , 2009).…”

Section: Introductionmentioning

confidence: 99%

Tp53 deletion in B lineage cells predisposes mice to lymphomas with oncogenic translocations

et al. 2011

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Inactivating Tp53 mutations are frequent genetic lesions in human tumors that harbor genomic instability, including B lineage lymphomas with IG translocations. Antigen receptor genes are assembled and modified in developing lymphocytes by RAG/AID-initiated genomic rearrangements that involve the induction of DNA double strand breaks (DSBs). Although TP53 inhibits the persistence of DSBs and induces apoptosis to protect cells from genomic instability and transformation, the development of spontaneous tumors harboring clonal translocations has not been reported in mice that only lack wild-type Tp53 protein or express Tp53 mutants. Tp53-deficient (Tp53 À/À ) mice succumb to T lineage lymphomas lacking clonal translocations but develop B lymphoid tumors containing immunoglobulin (Ig) translocations upon combined inactivation of DSB repair factors, RAG mutation or AID overexpression; mice expressing apoptosis-defective Tp53 mutants develop B cell lymphomas that have not been characterized for potential genomic instability. As somatic rather than germline inactivating mutations of TP53 are typically associated with human cancers and Tp53 deletion has cellular context dependent effects upon lymphocyte transformation, we generated mice with conditional Tp53 deletion in lineage-committed B lymphocytes to avoid complications associated with defective Tp53 responses during embryogenesis and/or in multilineage potential cells and, thereby, directly evaluate the potential physiological role of Tp53 in suppressing translocations in differentiated cells. These mb1-cre:Tp53 flox/flox mice succumbed to lymphoid tumors containing Ig gene rearrangements and immunophenotypes characteristic of B cells from various developmental stages. Most mb1-cre: Tp53 flox/flox tumors harbored clonal translocations, including Igh/c-myc or other oncogenic translocations generated by the aberrant repair of RAG/AID-generated DSBs.Our data indicate that Tp53 serves critical functions in B lineage lymphocytes to prevent transformation caused by translocations in cell populations experiencing physiological levels of RAG/AID-initiated DSB intermediates, and provide evidence that the somatic TP53 mutations found in diffuse large B-cell lymphoma and Burkitt's lymphoma may contribute to the development of these human malignancies.

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“…Indeed, DDR factor inactivation in mature B lymphocytes is accompanied by chromosomal translocations that occur during CSR in 53BP1 -/- [59,60] and H2AX -/-[61] mice. A very elegant recent study demonstrated that AID-induced DNA-dsb can associate to DNA-dsb generated by other experimental means, such as through IsceI endonuclease digestion, thus recapitulating the formation of a chromosomal translocation [62].…”

Section: Nhej and Csrmentioning

confidence: 99%

DNA repair and the immune system: From V(D)J recombination to aging lymphocytes

et al. 2007

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B and T lymphocytes are exposed to various genotoxic stresses during their life, which originate from programmed molecular mechanisms during their development and maturation or are secondary to cellular metabolism during acute phases of cell proliferation and activation during immune responses. How lymphocytes handle these multiple genomic assault has become a focus of interest over the years, perhaps beginning with the identification of the murine scid model in the early 80s when it was recognized that DNA repair deficiencies had profound consequences on the immune system. In this respect, the immune system represents an ideal model to study DNA damage responses (DDR) and the survey of immune deficiency conditions in humans or the development of specific animal models provided many major contributions in our understanding of the various biochemical pathways at play during DDR in general. Although the role of DNA repair in the early phases of B and T cell development has been analyzed thoroughly, the role of these functions in various aspects of the mature immune system (homeostasis, immunological memory, ageing) is less well understood. Lastly, the analysis of DNA repair in the immune system has provided many insights in the more general understanding of cancer. IntroductionAll living organisms are exposed to endogenous and environmental genotoxic stresses causing DNA injuries. Among these lesions, DNA double-strand breaks (DNAdsb) are considered as the most harmful. Unrepaired DNA damage can lead to mutation, cancer, or cell death. Several cellular responses are triggered, in what is called the DNA damage response (DDR), to handle DNA lesions (Fig. 1). The purpose of this review is not to go in the depth of the various biochemical pathways that constitute the DDR, as this aspect has been covered elsewhere [1], but rather to discuss, in an historical way, how the immune system depends on these pathways on one hand, and how studies of the immune system have been instrumental in the better understanding of some of these pathways, in particular the non-homologous end joining (NHEJ) pathway. Indeed, the immune system is the place of many genotoxic stresses that happen at various time points during the development and maturation of lymphocytes (Fig. 2). These DNA We discuss here the links that exist between the immune system and the DDR with the standpoint of the lymphocyte lifespan, from birth to ageing, and discuss the consequences of DNA repair defects on the integrity of the immune system. Development of the immune system V(D)J recombinationB and T lymphocytes respond to foreign pathogens through specialized antigenic receptors, the BCR and TCR, respectively. The required diversity of these receptors is ensured by the V(D)J recombination process (Fig. 3), which assembles previously scattered variable (V), diversity (D), and joining (J) encoding gene segments through a specialized somatic DNA rearrangement mechanism [2]. The reaction is initiated by the lymphoid-specific factors Rag1 and Rag2, which specifically...

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Role of genomic instability and p53 in AID-induced c-myc–Igh translocations

Cited by 319 publications

References 31 publications

AID and RAG1 do not contribute to lymphomagenesis in Eμ c-myc transgenic mice

AID and RAG1 do not contribute to lymphomagenesis in Eμ c-myc transgenic mice

Tp53 deletion in B lineage cells predisposes mice to lymphomas with oncogenic translocations

DNA repair and the immune system: From V(D)J recombination to aging lymphocytes

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