The RAG-1/2 endonuclease causes genomic instability and controls CNS complications of lymphoblastic leukemia in p53/Prkdc-deficient mice

Gladdy, Rebecca A.; Taylor, Michael D.; Williams, Christine; Grandal, Ildiko; Karásková, Jana; Squire, Jeremy A.; Rutka, James T.; Guidos, Cynthia J.; Danska, Jayne S.

doi:10.1016/s1535-6108(02)00236-2

Cited by 72 publications

(95 citation statements)

References 66 publications

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“…Images were captured using a LAMBDA LS light source from Sutter Instrument, and a COOL-1300QS camera ASI (ASI, Vista, CA, USA) then analyzed and managed through Case Data Manager Version 5.5 configured by ASI. (Zhu et al, 2002;Bassing et al, 2003;Celeste et al, 2003a;Gladdy et al, 2003;Rooney et al, 2004). Tumor #61 contained a disrupted c-myc locus (Figure 3e) but lacked translocations detectable by spectral karyotyping ( Table 1), suggesting that a genomic deletion involving the 5 0 end of the c-myc locus occurred on one allele.…”

Section: Resultsmentioning

confidence: 97%

“…First, Tp53 induces apoptosis of NHEJdeficient lymphocytes with un-repaired RAG DSBs and inhibits persistence of RAG DSBs outside of G1 phase in NHEJ-sufficient thymocytes Dujka et al, 2010). Second, germline NHEJ/Tp53-deficient mice succumb to pro-B lymphomas with RAG-dependent Igh/c-myc or Igh/N-myc translocations (Difilippantonio et al, 2002;Zhu et al, 2002;Gladdy et al, 2003;Rooney et al, 2004). Third, Tp53 À/À mice expressing a RAG1 mutant that exhibits defects in DNA end joining develop thymic lymphomas with clonal antigen receptor locus translocations (Giblin et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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“…However, a limitation is that mouse studies do not allow a precise dissection and separation of distinct endpoints such as chromosomal instability and survival. The majority of multiple pathway analysis using mice has focused on genetic crosses involving p53 (see for example [30][31][32][33][34]). Since p53 has critical roles in apoptosis and cell cycle checkpoint arrest, the interplay between defined pathways cannot be established.…”

Section: Other Studies Examining the Interplay Between Damage Responsmentioning

confidence: 99%

Contribution of DNA repair and cell cycle checkpoint arrest to the maintenance of genomic stability

2006

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Article (Unspecified) http://sro.sussex.ac.uk Jeggo, P. A. and Lobrich, M. (2006) Contribution of DNA repair and cell cycle checkpoint arrest to the maintenance of genomic stability. DNA Repair, 5 (9-10). pp. 1192 -1198 . ISSN 1568 This version is available from Sussex Research Online: http://sro.sussex.ac.uk/587/ This document is made available in accordance with publisher policies and may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the URL above for details on accessing the published version. Copyright and reuse:Sussex Research Online is a digital repository of the research output of the University.Copyright and all moral rights to the version of the paper presented here belong to the individual author(s) and/or other copyright owners. To the extent reasonable and practicable, the material made available in SRO has been checked for eligibility before being made available.Copies of full text items generally can be reproduced, displayed or performed and given to third parties in any format or medium for personal research or study, educational, or not-for-profit purposes without prior permission or charge, provided that the authors, title and full bibliographic details are credited, a hyperlink and/or URL is given for the original metadata page and the content is not changed in any way. DNA damage response mechanisms encompass pathways of DNA repair, cell cycle checkpoint arrest and apoptosis. Together, these mechanisms function to maintain genomic stability in the face of exogenous and endogenous DNA damage. ATM is activated in response to double strand breaks and initiates cell cycle checkpoint arrest. Recent studies in human fibroblasts have shown that ATM also regulates a mechanism of end-processing that is required for a component of double strand break repair. Human fibroblasts rarely undergo apoptosis after ionising radiation and, therefore, apoptosis is not considered in our review. The dual function of ATM raises the question as to how the two processes, DNA repair and checkpoint arrest, interplay to maintain genomic stability. In this review, we consider the impact of ATM's repair and checkpoint functions to the maintenance of genomic stability following irradiation in G2. We discuss evidence that ATM's repair function plays little role in the maintenance of genomic stability following exposure to ionising radiation. ATM's checkpoint function has a bigger impact on genomic stability but strikingly the two damage response pathways co-operate in a more than additive manner. In contrast, ATM's repair function is important for survival post irradiation.Introduction.

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“…3 However, in some cases, B-ALL still occurs when Rag activity is absent and IgH/c-myc translocation is suppressed. [4][5][6][7] Similarly, in an E -c-myc transgenic mouse model, loss of Rag1 increased (rather than suppressed) the incidence of B-cell lymphoma, although the mechanism has not been clarified. 8 Thus, it is likely that both aberrant Rag1 activity and Rag1 deficiency contribute to ALL, albeit with different underlying mechanisms and target cell populations.…”

Section: Introductionmentioning

confidence: 99%

Loss of p19Arf in a Rag1−/− B-cell precursor population initiates acute B-lymphoblastic leukemia

Hauer

Mullighan

Morillon

et al. 2011

Blood

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In human B-acute lymphoblastic leukemia (B-ALL), RAG1-induced genomic alterations are important for disease progression. However, given that biallelic loss of the RAG1 locus is observed in a subset of cases, RAG1's role in the development of B-ALL remains unclear. We chose a p19Arf ؊/؊ Rag1 ؊/؊ mouse model to confirm the previously published results concerning the contribution of CDKN2A (p19ARF /INK4a) and RAG1 copy number alterations in precursor B cells to the initiation and/or progression to B-acute lymphoblastic leukemia (B-ALL). In this murine model, we identified a new, Rag1-independent leukemiainitiating mechanism originating from a Sca1 ؉ CD19 ؉ precursor cell population and showed that Notch1 expression accelerates the cells' self-renewal capacity in vitro. In human RAG1-deficient BM, a similar CD34 ؉ CD19 ؉ population expressed p19ARF. These findings suggest that combined loss of p19Arf and Rag1 results in B-cell precursor leukemia in mice and may contribute to the progression of precursor B-ALL in humans. (Blood. 2011;118(3):544-553)

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The RAG-1/2 endonuclease causes genomic instability and controls CNS complications of lymphoblastic leukemia in p53/Prkdc-deficient mice

Cited by 72 publications

References 66 publications

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

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

Contribution of DNA repair and cell cycle checkpoint arrest to the maintenance of genomic stability

Loss of p19Arf in a Rag1−/− B-cell precursor population initiates acute B-lymphoblastic leukemia

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