Suppression of thymic lymphomas and increased nonthymic lymphomagenesis in Trp53‐deficient mice lacking inducible nitric oxide synthase gene (original) (raw)
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Cellular context-dependent effects of H2ax and p53 deletion on the development of thymic lymphoma
Blood, 2010
H2AX and Artemis each cooperate with p53 to suppress lymphoma. Germline H2ax−/−p53−/− mice die of T-cell receptor-β− (TCR-β−) thymic lymphomas with translocations and other lesions characteristic of human T-cell acute lymphoblastic leukemia. Here, we demonstrate that mice with inactivation of H2ax and p53 in thymocytes die at later ages to TCR-β− or TCR-β+ thymic lymphomas containing a similar pattern of translocations as H2ax−/−p53−/− tumors. Germline Artemis−/−p53−/− mice die of lymphomas with antigen receptor locus translocations, whereas Artemis−/−H2ax−/−p53−/− mice die at earlier ages from multiple malignancies. We show here that Artemis−/− mice with p53 deletion in thymocytes die of TCR-β− tumors containing Tcrα/δ translocations, other clonal translocations, or aneuploidy, as well as Notch1 mutations. Strikingly, Artemis−/− mice with H2ax and p53 deletion in thymocytes exhibited a lower rate of mortality from TCR-β− tumors, which harbored significantly elevated levels of genom...
Inducible nitric oxide synthase-mediated proliferation of a T lymphoma cell line
Nitric Oxide-biology and Chemistry - NITRIC OXIDE-BIOL CHEM, 2003
Nitric oxide (NO)-derived from T lymphocytes in an autocrine fashion can modulate events in the cell. However, the exact role of NO on the control of lymphocyte growth is controversial since both stimulation and inhibition have been demonstrated. Nitric oxide synthase (NOS) activity in normal and tumor T lymphocyte proliferation was studied here. Resting normal T lymphocytes displayed low levels of NOS activity that were slightly increased upon mitogenic stimulation. In contrast, BW5147 T lymphoma cells displayed higher basal levels than normal T lymphocytes that were significantly augmented when induced to proliferate. This activity was slightly modified in the presence of the calcium chelator EGTA and was blocked by competitive and irreversible NOS inhibitors, as well as by selective blockers of iNOS. Furthermore, tumor but not normal cell proliferation was impaired by NOS and iNOS blockers, while a calcium blocker only affected normal cell growth. iNOS expression, both at the pro...
Cancer Letters, 2008
TNF plays diverse and contrasting roles in cancer, promoting skin carcinogenesis and metastasis, but also possessing potent antitumor effects in mice. TNF via TNFR1 axis induces NFjB, and may contribute to inflammation-facilitated neoplasia. On the other hand, lymphomas are cited as rare complications of anti-TNF therapy in humans. In order to address possible modulating role of TNF and of a related cytokine, LTa, in spontaneous tumorigenesis, we compared mice with p53-TNF, p53-LTa, p53-TNFR1 and p53-TNF-LT combined deficiencies. Unexpectedly, neither of these mice showed significant modulation of their survival or shift in the spectrum of emerging tumors, as compared to p53-deficient mice, arguing against direct link between TNF blockade and lymphoma development.
Changes in protein expression in p53 deleted spontaneous thymic lymphomas
Experimental Cell Research, 2004
By the use of high-resolution two-dimensional gel electrophoresis and computerized image analysis we investigated and compared the expression of cellular proteins from p53 positive (+/+) mouse thymocytes, p53À/À thymocytes before neoplastic transformation, and from cell lines derived from two spontaneous p53À/À thymic lymphomas, SM5 and SM7. A total of around 1500 proteins were detected on individual gels. Only changes in protein expression by a factor of 2 or more were considered. In the thymic lymphoma cells 3 -5% of the proteins were found to be differentially regulated when compared with the protein expression in p53+/+ and p53À/À thymocytes. Only a minority (13 proteins) of the quantitatively changed proteins were common for the two thymic lymphoma cell lines, suggesting that the p53 deficiency mainly results in genetic dysfunctions which are individual for a given tumor. Two of the detected proteins increased their expression levels by more than 10 times from the p53+/+ to the p53À/À thymocytes and these high expression levels were also found in thymic lymphomas. The two proteins were identified by mass spectrometry as acidic ribosomal phosphoprotein P0 and a 33-kDa protein with a primary structure containing motifs of the glyoxalase -bleomycin resistance protein family (MDR) as deduced from the cDNA. D
Cancer Research
We have investigated stages of thymic lymphoma development in radiation and A'-methylnitrosourea (NMU)-treated C57BL/6J mice. The lymphoma cell was identified serologically as a cortical population bear ing Ml 1 -M1",H-2K1",and IL-2R* surface markers. According to these parameters in C57BL/6J mice the lymphoma cell was the same regardless of inducing agent or activated oncogene (ras or non-nu). Transforming activity in the radiation and NMU-induced tumors was analyzed using both the nude mouse tumorigenicity assay and the focus-forming assay. 8/10 NMU-induced tumors and 12/15 radiation-induced tumors showed transforming activity in the tumorigenicity assay. Southern blot analysis of the nude mouse transformants demonstrated K-rav transforming se quences in eight of eight NMU-induced lymphoma DNAs, two of 12 radiation-induced lymphoma DNAs and N-ra.vtransforming sequences in five of 12 radiation-induced lymphoma DNAs. The nini-ras transforming activity in five DNAs from radiation-induced thymic lymphomas indicates the presence of an unidentified oncogene(s) in these tumors. Staging of thymic lymphoma development in this animal model system will allow the study of oncogene activation early in the course of carcinogen-induced disease. These results also emphasize the high sensitivity of the nude mouse assay to score for activated oncogenes and might also indicate a high frequency of K-ras activation in NMU-induced lymphomas in C57BL/6J mice.
Proceedings of The National Academy of Sciences, 2003
We have generated mice null for IFN- and report the diverse consequences of IFN- for both the innate and adaptive arms of immunity. Despite no abnormalities in the proportional balance of CD4 and CD8 T cell populations in the peripheral blood, thymus, and spleen of IFN- ؊/؊ mice, activated lymph node and splenic T lymphocytes exhibit enhanced T cell proliferation and decreased tumor necrosis factor ␣ production, relative to IFN- ؉/؉ mice. Notably, constitutive and induced expression of tumor necrosis factor ␣ is reduced in the spleen and bone marrow (BM) macrophages, respectively, of IFN- ؊/؊ mice. We also observe an altered splenic architecture in IFN- ؊/؊ mice and a reduction in resident macrophages. We identify a potential defect in B cell maturation in IFN- ؊/؊ mice, associated with a decrease in B220 ؉ve/high ͞CD43 ؊ve BM-derived cells and a reduction in BP-1, IgM, and CD23 expression. Circulating IgM-, Mac-1-, and Gr-1-positive cells are also substantially decreased in IFN- ؊/؊ mice. The decrease in the numbers of circulating macrophages and granulocytes likely reflects defective maturation of primitive BM hematopoiesis in mice, shown by the reduction of colony-forming units, granulocytemacrophage. We proceeded to evaluate the in vivo growth of malignant cells in the IFN- ؊/؊ background and give evidence that Lewis lung carcinoma-specific tumor growth is more aggressive in IFN- ؊/؊ mice. Taken altogether, our data suggest that, in addition to the direct growth-inhibitory effects on tumor cells, IFN- is required during different stages of maturation in the development of the immune system.
Cancer Cell, 2006
Mice deficient in the DNA damage sensor P53 display normal T cell development but eventually succumb to thymic lymphomas. Here, we show that inactivation of the TCR b gene enhancer (Eb) results in a block of T cell development at stages where recombination-activating genes (RAG) are expressed. Introduction of the Eb mutation into p53 2/2 mice dramatically accelerates the onset of lethal thymic lymphomas that harbor RAG-dependent aberrant rearrangements, chromosome 14 and 12 translocations, and amplification of the chromosomal region 9A1-A5.3. Phenotypic and genetic analyses suggest that lymphomas emerge through a normal thymocyte development pathway. These findings provide genetic evidence that block of lymphocyte development at stages with RAG endonuclease activity can provoke lymphomagenesis on a background with deficient DNA damage responses.