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

Nepal, Rajeev M.; Zaheen, Ahmad; Basit, Wajiha; Li, L; Berger, Stuart A.; Martín, Alberto

doi:10.1038/onc.2008.111

Cited by 30 publications

(41 citation statements)

References 28 publications

(50 reference statements)

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“…For example, nuclear factor-kB, the tumorsuppressor Ink4c, the death protein Apaf1/caspase9, as well as the DNA-modifying enzymes AID and Rag have all been shown to be dispensable for c-Myc-driven tumorigenesis (Scott et al, 2004;Keller et al, 2005;Kotani et al, 2007;Nilsson et al, 2007;Nepal et al, 2008). However, our data show that signals through IL7Ra Y449, such as STAT5, can regulate transformation in this lymphoma model.…”

Section: Il-7ra Y449 Signals Contribute To Lymphomagenesis Lc Osbornementioning

confidence: 59%

“…These data explain the fact that rag1 À/À mice, which normally have a developmental block at the pro-B-cell stage and therefore have dramatically decreased numbers of Em-myc lymphoma precursors, not only developed Em-myc-induced pre-B-cell lymphomas but also showed earlier tumor onset (Nepal et al, 2008). Similarly, the loss of the BCR signaling effector phospholipaseCg2 shortens the lifespan of Em-myc mice due to an increase in BM pre-B cells that are hypersensitive to IL-7-induced proliferation (Wen et al, 2006).…”

Section: Il-7ra Y449 Signals Contribute To Lymphomagenesis Lc Osbornementioning

confidence: 68%

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Selective ablation of the YxxM motif of IL-7Rα suppresses lymphomagenesis but maintains lymphocyte development

et al. 2010

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Tumor progression is a multiple step process in which, in addition to oncogenic mutation, other supporting factors can contribute to transformation. The role these factors have in cancer is an open question. Using the El-myc model of B-cell transformation, we evaluated the contribution of the cytokine interleukin-7 (IL-7) in supporting lymphomagenesis. We have previously shown that disruption of the Y449xxM motif of the IL-7 receptor alpha (IL-7Ra) in a knock-in mouse model (IL-7Ra 449F ) has minor effects on lymphocyte production, but interferes with the activation of survival effectors. To address the hypothesis that targeted signal ablation would selectively affect lymphocyte transformation, IL-7Ra 449F mice were crossed with two lymphomagenesis models, transgenic (Tg) IL-7 and El-myc mice. We found that the loss of IL-7Ra Y449 signaling prevented Tg IL-7-mediated T-and B-lymphocyte transformation and decreased the development of El-myc-induced B-cell tumors. We showed that the IL-7Ra 449F mutation prevented increased survival of Tg IL-7 CD8 T cells, and decreased viability of bone marrow progenitor B cells, as well as Elmyc-induced proliferation. This study shows that IL-7Ra Y449 is important for lymphocyte transformation, and that unlike deficiencies in pre-B cell receptor signaling, Myc overexpression cannot compensate for the loss of IL-7Ra signals in early B-cell development.

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Section: Il-7ra Y449 Signals Contribute To Lymphomagenesis Lc Osbornementioning

confidence: 59%

Section: Il-7ra Y449 Signals Contribute To Lymphomagenesis Lc Osbornementioning

confidence: 68%

Selective ablation of the YxxM motif of IL-7Rα suppresses lymphomagenesis but maintains lymphocyte development

et al. 2010

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“…The cellular origin, developmental timing and molecular mechanism of oncogene activation and tumor suppressor gene inactivation can influence cancer predisposition and tumor phenotype. For example, wild-type and Rag1 À/À mice with C-MYC expression initiating in B and T lymphocyte lineages succumb at similar ages to B lymphoid tumors (Adams et al, 1985;Nepal et al, 2008); whereas, mice with C-MYC expression starting in hematopoietic stem cells develop T cell lymphomas, but succumb at later ages to both B and T lineage tumors when on a Rag1 À/À background (Smith et al, 2005). In addition, mice with H2ax and Tp53 deletion initiating in lineage-committed T cells develop immature T-cell lymphomas more rapidly and of later developmental stages than germline H2ax À/À Tp53 À/À mice (Yin et al, 2010).…”

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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“…First, loss of the RAG1 locus occurs with significant frequency in precursor B-ALL, 2 and Rag1 deficiency contributes to leukemogenesis in mouse models only when combined with secondary oncogene activation or tumor suppressor gene inactivation. 8,9 Second, p19ARF loss-of-function mutations are involved in a high percentage of human precursor B-cell leukemia (16 of 47 tested cases in Mullighan et al 2 ). One possible explanation for the predisposition to precursor B-ALL in the absence of RAG1 is that the Rag-deficiency-induced arrest in B-cell differentiation leads to alterations in the phenotype and frequency of the various lymphoid precursor populations in the BM.…”

Section: Introductionmentioning

confidence: 99%

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

Cited by 30 publications

References 28 publications

Selective ablation of the YxxM motif of IL-7Rα suppresses lymphomagenesis but maintains lymphocyte development

Selective ablation of the YxxM motif of IL-7Rα suppresses lymphomagenesis but maintains lymphocyte development

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

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

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