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| 2. |
- Aad, G, et al.
(författare)
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- 2015
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swepub:Mat__t
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| 3. |
- Karlsson, Anneli, 1973-
(författare)
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Genetic Alterations in Lymphoma : with Focus on the Ikaros, NOTCH1 and BCL11B Genes
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cell proliferation is a process that is strictly regulated by a large number of proteins. An alteration in one of the encoding genes inserts an error into the regulative protein, which may result in uncontrolled cell growth and eventually tumor formation. Lymphoma is a cancer type originating in the lymphocytes, which are part of the body’s immune defence. In the present thesis, Znfn1a1, Notch1 and Bcl11b were studied; all involved in the differentiation of T lymphocytes. The three genes are located in chromosomal regions that have previously shown frequent loss of heterozygosity in tumor DNA.Ikaros is a protein involved in the early differentiation of T lymphocytes. In this thesis, mutation analysis of the Znfn1a1 gene in chemically induced murine lymphomas revealed point mutations and homozygous deletions in 13 % of the tumors. All of the detected deletions lead to amino acid substitutions or abrogation of the functional domains in the Ikaros protein. Our results support the role of Ikaros as a potential tumor suppressor in a subset of tumors.Notch1 is a protein involved in many differentiation processes in the body. In lymphocytes, Notch1 drives the differentiation towards a T-cell fate and activating alterations in the Notch1 gene have been suggested to be involved in T-cell lymphoma. We identified activating mutations in Notch1 in 39 % of the chemically induced murine lymphomas, supporting the involvement of activating Notch1 mutations in the development of T-cell lymphoma.Bcl11b has been suggested to be involved in the early T-cell specification, and mutations in the Bcl11b gene has been identified in T-cell lymphoma. In this thesis, point mutations and deletions were detected in the DNA-binding zinc finger regions of Bcl11b in 15 % of the chemically induced lymphomas in C57Bl/6×C3H/HeJ F1 mice. A mutational hotspot was identified, where four of the tumors carried the same mutation. Three of the identified alterations, including the hotspot mutation in Bcl11b, increased cell proliferation when introduced in a cell without endogenous Bcl11b, whereas cell proliferation was suppressed by wild-type Bcl11b in the same cell line. Mutations in Bcl11b may therefore be an important contributing factor to lymphomagenesis in a subset of tumors.A germ line point mutation was identified in BCL11B in one of 33 human B-cell lymphoma patients. Expression of BCL11B in infiltrating T cells was significantly lower in aggressive compared to indolent lymphomas, suggesting that the infiltrating T cells may affect the B-cell lymphomas.
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| 4. |
- Karlsson, Anneli, et al.
(författare)
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Point mutations and deletions in the Znfn1a1/Ikaros gene in chemically induced murine lymphomas
- 2002
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 62:9, s. 2650-2653
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Tidskriftsartikel (refereegranskat)abstract
- The Znfn1a1 gene encodes a zinc finger protein called Ikaros, which is criticalfor T-cell development and differentiation. The execution of normalfunction of Ikaros requires sequence-specific DNA binding, transactivation, and dimerization domains. In this study, exons 3–5 and exon 7 of the Znfn1a1 gene that encode the functional domains of Ikaros were analyzed for point mutations and deletions in murine lymphomas induced by 1,3-butadiene, 2',3'-dideoxycytidine, or phenolphthalein. Missense and frameshift mutations were identified in 11% (11 of 104) of the tumors. Interestingly, 8 of the mutations were identified in the NH2-terminal zinc finger motifs, which are crucial for the DNA-binding function of Ikaros. The other 3 samples carried frameshift mutations in exon 7 that resulted in truncations and abrogation of both transactivation and dimerization domains. One tumor with a missense mutation in the DNA-binding domain also displayed a 45-bp deletion in the dimerization domain. Southern analysis disclosed interstitial homozygous deletions in the functional domains of Ikaros in 4% (3 of 68) of the lymphomas examined. Allelic losses on markers surrounding the Znfn1a1 gene were detected in 27% (12 of 45) of the tumors analyzed. However, only 2 tumors with allelic losses also showed mutations in the Znfn1a1 gene, indicating that other tumor suppressor genes located on this region might be involved as well. Our results suggest inactivation of Ikaros in a subset of chemically induced lymphomas and additionally support the contention of tumor-suppressor activity for Ikaros.
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| 5. |
- Zhuang, Shi-Mei, 1965-, et al.
(författare)
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Frequent mutations of the Trp53,Hras1 and beta-catenin (Catnb) genes in 1,3-butadiene-induced mammary adenocarcinomas in B6C3F1 mice
- 2002
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 21:36, s. 5643-5648
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Tidskriftsartikel (refereegranskat)abstract
- DNAs from 1,3-butadiene-induced mammary adenocarcinomas of B6C3F1 mice were examined for mutations in the Trp53 gene, the ras gene family and several components of the Wnt signaling pathway, including ▀-catenin (Catnb), Apc and Axin. Trp53 mutations were detected in 41% (7 out of 17) of tumors. Each tumor with a Trp53 mutation also exhibited loss of the wildtype Trp53 allele, supporting the importance of Trp53 inactivation during development of these tumors. Analyses of the Hras1, Kras2 and Aras proto-oncogenes revealed Hras1 mutations in 53% (9 out of 17) of tumors. Seven of these mutations were a G?C transversion in Hras1 codon 13, consistent with a 1,3-butadiene-specific Kras2 mutation previously reported in several other tumor types. Mutation screens in Catnb exon 2, the Apc mutation cluster region and the Catnb-binding domain of the Axin gene identified Catnb missense mutations in 3 out of 17 (18%) tumors. In total, mutations of the Trp53, Hras1 and/or Catnb genes were identified in 15 out of 17 1,3-butadiene-induced mammary adenocarcinomas. These results indicate that multiple genetic pathways are disrupted in chemically induced mammary tumors, and that studies in mouse models may help to understand the etiology of human breast cancers.
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| 6. |
- Zhuang, Shi-Mei, et al.
(författare)
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Genetic analysis of Raf1, Mdm2, c-Myc, Cdc25a and Cdc25b proto-oncogenes in 2′,3′-dideoxycytidine- and 1,3-butadiene-induced lymphomas in B6C3F1 mice
- 2000
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Ingår i: Mutation Research. - 1383-5742 .- 1388-2139. ; 452:1, s. 19-26
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Tidskriftsartikel (refereegranskat)abstract
- We have previously identified activation of ras proto-oncogenes and inactivation of tumor suppressor genes including p53, p16INK4a and p15INK4b in 2′,3′-dideoxycytidine (ddC)- and/or 1,3-butadiene (BD)-induced lymphomas derived from B6C3F1 (C57BL/6xC3H/He) mice, indicating that alterations of ras signaling pathway, p53 and pRb growth control pathways are important in the development of these chemically induced lymphomas. However, there is still a subset of tumors that displayed no changes in these genes. Thus, we investigated whether the Raf1, Mdm2, c-Myc, Cdc25a and Cdc25b proto-oncogenes, which are implicated in the ras or p53 or pRb pathways, are alternative oncogenic target genes. Analyses of gross genomic alterations by Southern blots failed to reveal rearrangement or amplification in any of the tumors examined. Frequent point mutations on the substrate binding domain of the Raf1 gene has been reported in 1-ethyl-1-nitrosourea (ENU)-induced murine lymphomas and lung tumors, along with a conspicuous lack of ras mutations [U. Naumann, I. Eisenmann-Tappe, U.R. Rapp, The role of raf kinases in development and growth of tumors, Recent Results Cancer Res., 143 (1997) 237–244]. To investigate whether Raf1 mutation is involved in our set of tumor especially those without ras mutations, the PCR-based single-strand conformation analyses (SSCA) and direct DNA sequencing were employed. No mutations but four genetic polymorphisms between C57BL/6 and C3H/He were found, with two of them reported as point mutations previously (op. cit.). The polymorphisms were utilized for allelic loss study of Raf1 locus. Losses of heterozygosity were found in six of 31 BD-induced lymphomas. These results indicate that genetic alterations of c-Myc, Cdc25, Raf1 and Mdm2 proto-oncogenes may not be involved in the development of ddC- and BD-induced lymphomas and the inactivation of tumor suppressor gene(s) located close to Raf1 gene might be important in the development of a subset of BD-induced lymphomas.
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| 7. |
- Zhuang, Shi-Mei, 1965-
(författare)
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Molecular genetic alterations in chemically-induced lymphomas
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Lymphoma is one of the most common malignancies in humans. Its incidence has increased rapidly in the past 30 years. However, the molecular mechanisms underlying the development of lymphomas are largely unknown.Environmental carcinogens play an important role in tumorigenesis. 1,3-butadiene (BD) and 2~,3-dideoxycytidine (ddC) are two carcinogens to which humans are exposed. Cancer bioassays in mice have revealed that both BD and ddC induce high frequencies of lymphomas. The present study provides a genetic dissection of these chemically-induced lymphomas, with a focus on identification of potential turner suppressor loci and genetic alterations in genes involved in the pRb, p53 and Ras/Raf pathways. These pathways are important in the control of cell proliferation.Approximately 87% of BD-induced and 75% of ddC-induced lymphomas show allelic losses or mutations in genes examined. Similar frequencies for inactivation of the p53 pathway were observed in BD- and ddC-induced tumors, whereas disruption of the pRb pathway is more common in ddC-induced lymphomas. On the other hand, BD-induced tumors display more frequent activation of the Ras/Raf pathway. These data indicate the genotoxicity of both ddC and BD, and also confirm the carcinogenicity of these chemicals at a molecular level.This study also reveals that different genetic alterations occur in distinct stages of the development of BD-induced lymphomas. Ras mutations were detected in tumors derived from mice exposed to BD for only 26 weeks or at a rather low concentration (20 ppm), suggesting that ras mutations may occur early in tumor formation. In contrast, all six tumors with aberrations of p53 occurred in the high dose (625 ppm), continuous long-term exposure group, and these tumors appear to have a more aggressive phenotype, indicating that inactivation of p53 may be a late event, associated with progression of BD-induced lymphomas. Furthermore, two or more genetic alterations were found in 67% of tumors from the 625 ppm dose group and in only 46% of lymphomas derived from mice exposed to s312 ppm of BD. In addition, more than five genetic aberrations occurred only in the 625 ppm dose group. These results support the contention that there is a dose-dependent increase of genetic alterations in BD-induced tumors.The mutational pattern resulting from carcinogen-exposure has been observed in both human and animal turners. In the present study, the specific K-ras codon 13 CGC mutation and allelic loss of the Rafl locus on chromosome 6 were detected only in BD-induced lymphomas, while frequent allelic loss of the telomeric region of chromosome 2 was observed only in ddC-induced tumors, suggesting an agent-specific effect.The genome-wide screen of allelic losses revealed that multiple potential tumor suppressor genes contribute to the development of BD- and ddC-induced lymphomas. Moreover, most of the identified regions with frequent allelic losses carry unknown tumor suppressor genes, whose isolation and identification are of great interest for further investigation.
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| 8. |
- Zhuang, Shi-Mei, 1965-, et al.
(författare)
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Mutation analysis of the pRb pathway in 2',3'-dideoxycytidine- and 1,3-butadiene-induced mouse lymphomas
- 2000
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Ingår i: Cancer Letters. - 0304-3835 .- 1872-7980. ; 152:2, s. 129-134
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Tidskriftsartikel (refereegranskat)abstract
- The pRb pathway plays a key role in controlling the G1/S transition in cell cycle progression. Aberrations of various components of the pRb pathway, such as retinoblastoma protein and its upstream actors including cyclin D1, cyclin dependence kinase-4 and p16/p15 cyclin dependent kinase inhibitors, have been reported in a variety of human tumors. Furthermore, the alterations of retinoblastoma protein and its upstream components often occur in a reciprocal manner. Previously, we have reported frequent inactivation of the Cdkn2a/Cdkn2b loci encoding p16/p15 cyclin dependent kinase inhibitors in a subset of 2',3'-dideoxycytidine- and 1,3-butadiene-induced mouse lymphomas (S.-M. Zhuang, A. Schippert, A. Haugen-Strano, R.W. Wiseman, P. Soderkvist, Inactivation of p16(INK4a)-a, p16(INK4a)-▀ and p15(INK4b) genes in 2',3'-dideoxycytidine- and 1,3-butadiene-induced lymphomas, Oncogene 16 (1998) 803-808), indicating the involvement of pRb pathway in lymphomagenesis. To investigate whether alteration of other components in pRb pathway is an alternative mechanism underlying the development of these chemically induced lymphomas, we have examined the genetic status of Rb1, Ccnd1 and Cdk4 genes that encode retinoblastoma protein, cyclin D1 and cyclin dependence kinase-4, respectively. Gross alterations of the Rb1, Ccnd1, and Cdk4 genes were not detected by Southern analysis in any of the tumors examined. In addition, single-strand conformation analysis failed to reveal point mutations in the Cdk4 amino terminal domain that is important for its association with Cdkn2a gene products. These results indicate that the mechanisms underlying the development of 2',3'-dideoxycytidine- and 1,3-butadiene-induced lymphomas involve inactivation of p16/p15 cyclin-dependent kinase inhibitors but not genomic alterations of the Rb1, Ccnd1 and Cdk4 genes. Copyright (C) 2000 Elsevier Science Ireland Ltd.
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