Unexpected effects of the severe combined immunodeficiency mutation on murine lymphomagenesis.

Lieberman, Miriam; Hansteen, Gun; Waller, Edmund K.; Sen‐Majumdar, Anis

doi:10.1084/jem.176.2.399

Cited by 22 publications

(8 citation statements)

References 21 publications

(25 reference statements)

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“…Tumors of host origin may develop as the consequence of exposure of thymocytes or BM progenitors to ionizing radiation, as described for SCID mice. 43 On the other hand, tumors of donor origin may result from an intrinsic susceptibility of ADA-deficient cells or an ineffective immunologic surveillance, as hypothesized for lymphomas developing in ADA-SCID patients receiving PEG-ADA. 2,45 Importantly, we found no evidence of insertional mutagenesis induced by LV integrated at high copies in these tumors.…”

Section: Discussionmentioning

confidence: 99%

“…It is well established that SCID mice with defects in recombinase system have a high incidence of thymic lymphomas which is dramatically increased by irradiation, 43,44 but no information is available in ADA Ϫ/Ϫ mice due to their short life span. Our results suggest that in the context of nonlethal irradiation and BMT also ADA Ϫ/Ϫ mice show a high risk of developing lymphomas.…”

Section: Discussionmentioning

confidence: 99%

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Ex vivo gene therapy with lentiviral vectors rescues adenosine deaminase (ADA)–deficient mice and corrects their immune and metabolic defects

Mortellaro

Hernández

Guerrini

et al. 2006

Blood

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ex vivo gene therapy with lentiviral vectors rescues adenosine deaminase (ADA)–deficient mice and corrects their immune and metabolic defects

Mortellaro

Hernández

Guerrini

et al. 2006

Blood

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“…The target cell type and the events occurring in the course of lymphomagenesis within the infected thymus have yet to be fully defined. The availability of monoclonal antibodies against T-cell differentiation antigens (3,25) and the transformationassociated antigen 1C1 1 (28,41) and of hybridization probes to TCR genes (7) have made possible an analysis of surface marker phenotypes of RadLV-infected, preleukemic, and/or leukemic thymocytes. Using a monoclonal antibody against the gp7O glycoprotein of RadLV, we present evidence that the earliest cell type in the RadLV-infected thymus to express viral gp7O is lCl11 and that a subset of these cells express high levels of the TCR-CD3 complex.…”

mentioning

confidence: 99%

Radiation leukemia virus-induced thymic lymphomas express a restricted repertoire of T-cell receptor V beta gene products

Sen‐Majumdar

Hansteen

Marian

et al. 1994

J Virol

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We have investigated the phenotypic changes that take place during the process of neoplastic transformation in the thymocytes of C57BL/Ka mice infected by the radiation leukemia virus (RadLV). By the combined use of antibodies against the envelope glycoprotein gp7O of RadLV, the transformation-associated cell surface marker lC1l, and the CD3-T-cell receptor (TCR) complex, we found that in the RadLV-infected thymus, the earliest expression of viral gp7O is in lCllhi cells; a small but significant percentage of these cells also express CD3. A first wave of viral replication, manifested by the expression of high levels of gp7O in thymocytes (over 70% positive), reaches a peak at 2 weeks; during this period, no significant changes are observed in the expression of IC11 or CD3. The population of gp70+ cells is drastically reduced at 3 to 4 weeks after infection. However, a second cohort of gp70+ cells appears after 4 weeks, and these cells express high levels of lCll and TCR determinants as well. RadLV-induced lymphomas differ from normal thymocytes in their CD4 CD8 phenotype, with domination by one or more subsets. Characterization of TCR gene rearrangements in RadLV-induced lymphomas shows that most of these tumors are clonal or oligoclonal with respect to the JP2 TCR gene, while the Jjll TCR gene is rearranged in a minority (4 of 11) of lymphomas. TCR VP repertoire analysis of 12 tumors reveals that 6 (50%o) express exclusively the V,I6 gene product, 2 (17%) are V05', and 1 (8%) each are VP8+ and VP9+. In normal C57BL/Ka mice, VPI6 is expressed on 12%, VII5 is expressed on 9%, V,B8 is expressed on 22%, and Vj89 is expressed on 4% of TCRhi thymocytes. Thus, it appears that RadLV-induced thymic lymphomas are not randomly selected with respect to expressed TCR VP type. Exposure to ionizing radiation is known to induce lymphoid malignancy in humans; the incidence of acute lymphoblastic leukemia in particular has been shown to correlate with radiation dose (34). To facilitate investigation of the basic mechanisms by which radiation induces leukemia, Kaplan and colleagues developed a murine model (21, 22) which they used to define the parameters for T-cell transformation. Wholebody irradiation, administered in fractionated doses, was found to induce a high incidence (>90%) of thymus-dependent lymphomas in C57BL/Ka mice (22). A thymotropic and lymphomagenic retrovirus, the radiation leukemia virus (RadLV), was recovered from cell extracts of some of these lymphomas (29, 30). After serial in vivo passage, RadLV-induced thymic lymphomas were found to be similar in frequency, clinical aspects, and latency to those produced by radiation. Several lymphoma cell lines from RadLV-induced tumors were established in culture (27); one such cell line, BLNVL3, was used to

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“…However, in our SCID colony, Ͻ5% of SCID mice developed lymphoma by 2 years of age. Strikingly, lowdose (100 to 175 cGy) irradiation of newborn SCID mice induces thymic lymphoma, but not other tumors, with very high frequency and short latency (29,79,88). Mice harboring other mutations in DNA-PK or in KU70 were subsequently shown to spontaneously develop thymic lymphoma, but other tumor types have not been reported (48,59,73).…”

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confidence: 99%

Irradiation Promotes V(D)J Joining and RAG-Dependent Neoplastic Transformation in SCID T-Cell Precursors

Williams

Grandal

Vesprini

et al. 2001

Molecular and Cellular Biology

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Defects in the nonhomologous end-joining (NHEJ) pathway of double-stranded DNA break repair severely impair V(D)J joining and selectively predispose mice to the development of lymphoid neoplasia. This connection was first noted in mice with the severe combined immune deficient (SCID) mutation in the DNA-dependent protein kinase (DNA-PK). SCID mice spontaneously develop thymic lymphoma with low incidence and long latency. However, we and others showed that low-dose irradiation of SCID mice dramatically increases the frequency and decreases the latency of thymic lymphomagenesis, but irradiation does not promote the development of other tumors. We have used this model to explore the mechanistic basis by which defects in NHEJ confer selective and profound susceptibility to lymphoid oncogenesis. Here, we show that radiation quantitatively and qualitatively improves V(D)J joining in SCID cells, in the absence of T-cell receptor-mediated cellular selection. Furthermore, we show that the lymphocyte-specific endonuclease encoded by the recombinaseactivating genes (RAG-1 and RAG-2) is required for radiation-induced thymic lymphomagenesis in SCID mice. Collectively, these data suggest that irradiation induces a DNA-PK-independent NHEJ pathway that facilitates V(D)J joining, but also promotes oncogenic misjoining of RAG-1/2-induced breaks in SCID T-cell precursors.Lymphocytes require the faithful execution of DNA repair processes to generate a highly diverse repertoire of antigen receptors. The variable region exon of each T-cell receptor (TCR) and B-cell antigen receptor (BCR) gene is assembled by site-specific cleavage and rejoining of variable (V), diversity (D), and joining (J) gene segments in developing T and B lymphocytes. Tandem genomic arrays of dozens to hundreds of V, D, or J gene segments allow combinatorial diversification of the available germline repertoire during lymphocyte development to create a large number of clonally distinct VDJ or VJ genes. In addition, terminal deoxynucleotidal transferase (TdT), a lymphocyte-specific polymerase, inserts non-germline-encoded nucleotides at V(D)J junctions, providing additional somatic diversification of the available germline repertoire (30,44,67). Thus, V(D)J recombination endows T and B lymphocytes with the capacity to specifically recognize and destroy an almost infinite array of pathogens. However, DNA breaks are highly recombinogenic and must be repaired efficiently to maintain genomic stability and minimize the risk of oncogenic transformation (31,33,43,49,90,104). A high frequency of lymphoid tumors have chromosomal translocations involving antigen receptor genes (reviewed in reference 101), raising the question as to whether the V(D)J recombination process threatens genomic stability in lymphoid lineages.The molecular mechanism of V(D)J cleavage has recently been elucidated by elegant biochemical studies (reviewed in references 93 and 106). This process is mediated by the lymphoid-specific RAG-1 and RAG-2 proteins, which bind recombination signal sequences fl...

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Unexpected effects of the severe combined immunodeficiency mutation on murine lymphomagenesis.

Cited by 22 publications

References 21 publications

Ex vivo gene therapy with lentiviral vectors rescues adenosine deaminase (ADA)–deficient mice and corrects their immune and metabolic defects

Ex vivo gene therapy with lentiviral vectors rescues adenosine deaminase (ADA)–deficient mice and corrects their immune and metabolic defects

Radiation leukemia virus-induced thymic lymphomas express a restricted repertoire of T-cell receptor V beta gene products

Irradiation Promotes V(D)J Joining and RAG-Dependent Neoplastic Transformation in SCID T-Cell Precursors

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