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Notch1 is a frequent mutational target in chemically induced lymphoma in mouse
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
National Institute of Environmental Health Science, NC USA.
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2008 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 123, no 11, 2720-2724 p.Article in journal (Refereed) Published
Abstract [en]

Activating Notch1 mutations have been reported in human T-lineage acute lymphoblastic leukemia (T-ALL) and lymphomas from genetically modified mice. We report that Notch1 is a prevalent and major mutational target in chemically induced mouse lymphoma. The regions of the gene that are frequently mutated are the hterodimerization domain and the N-terminal ligand-binding region, important for protein stability, and (he polypeptide rich in proline, glutamate, serine and threonine WEST) domains, which is critical for protein degradation. Another gene, CDC4, is also involved in Notch1 degradation and shows frequent mutations. Mutations in the heterodimerization and the ligand-binding regions may cause ligand-independent signaling. whereas mutations preventing protein degradation result in accumulation of intracellular Notch1. We analyzed 103 chemical-induced mouse lymphomas for mutations in the Notch1 gene using single strand conformation analysis (SSCA) and DNA sequencing. Genetic alterations resulting in premature truncation of Notch I were identified in 28 tumors, whereas 8 revealed alterations in the heterodimerization and 16 harbored deletions in the ligand-binding region. Dideoxycytidine-induced lymphomas displayed the highest frequency of Notch1 mutations (49%). whereas in butadiene- and phenolphthalein-indced tumors showed lower frequencies (26 10%, respectively). In total, 26 novel and 3 previously reported mutations were detected. This report shows that Notch1 is a prevalent and major mtational target for 2,3-dideoxycytidine and butadiene-induced lymphoma..

Place, publisher, year, edition, pages
2008. Vol. 123, no 11, 2720-2724 p.
Keyword [en]
TAN-1, hN1, butadiene, dideoxycytidine, phenolphthalein
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-16112DOI: 10.1002/ijc.23832OAI: oai:DiVA.org:liu-16112DiVA: diva2:133192
Available from: 2009-01-08 Created: 2009-01-07 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Genetic Alterations in Lymphoma: with Focus on the Ikaros, NOTCH1 and BCL11B Genes
Open this publication in new window or tab >>Genetic Alterations in Lymphoma: with Focus on the Ikaros, NOTCH1 and BCL11B Genes
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Linköping University Electronic Press, 2008. 60 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1040
Keyword
Cell proliferation, Lymphoma, Znfn1a1, Notch1, Bcl11b, chromosomal regions, Ikaros, B-cell lymphomas
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-10694 (URN)978-91-7393-985-0 (ISBN)
Public defence
2008-02-15, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2008-01-30 Created: 2008-01-30 Last updated: 2015-11-19
2. Notch signalling in carcinogenesis: With special emphasis on T-cell lymphoma and colorectal cancer
Open this publication in new window or tab >>Notch signalling in carcinogenesis: With special emphasis on T-cell lymphoma and colorectal cancer
2009 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

The Notch signalling pathway is an evolutionary conserved pathway, named after the Notch receptors, Notch1-4 in mammals, which upon cell-cell contact and ligand binding releases the intracellular domain (NICD). NICD translocates into the nucleus where it binds the transcriptional repressor RBP-Jk, which together with co-activators belonging to the Mastermind-like family of proteins form a transcriptional activation complex. This complex activates genes controlling cell fate decision, embryonic development, proliferation, differentiation, adult homeostasis and stem cell maintenance. On the other hand, disrupted Notch signalling may result in pathological conditions like cancer, although the mechanisms behind the disruption are often complex and in many cases largely unknown.

Notch1 drives the lymphocyte differentiation towards a T-cell fate and activating mutations in the gene have been suggested to be involved in T-cell lymphoma. In paper I, genetic alterations in Notch1 and the Notch1 regulating gene CDC4 were investigated in tumours from murine T-cell lymphoma induced with phenolphthalein, 1,3-butadiene or 2’,3’-dideoxycytidine. We identified activating Notch1 mutations in 39% of the lymphomas, suggesting that Notch1 is an important target gene for mutations in chemically induced lymphomas.

While it is known that constitutively activated Notch signalling has a clear oncogenic function in several solid malignancies as well, the molecular mechanisms are less known in this context. Unpublished data of our lab, together with other recent studies, suggest that mutations of Notch and Notch-related genes per se are uncommon in solid malignancies including colorectal cancer, while a growing body of evidence indicates that aberrant Wnt/b-catenin signalling may result in pro-tumoural Notch activation in these contexts. In paper II, we therefore investigated potential transcriptional interactions between the Notch and Wnt signalling pathways in colorectal cancer cell lines. The proximal Notch and Wnt pathway gene promoters were bioinformatically identified and screened for putative TCF/LEF1 and RBP-Jk sites. In canonical Wnt signalling, Apc negatively regulates b-catenin leading to repression of TCF/LEF1 target genes. Upon repression of the Wnt pathway we observed that several genes in the Notch pathway, including Notch2, were transcriptionally downregulated. We also confirmed binding of Lef1 to Notch2 as well as other Notch pathway gene promoters and luciferase assays showed an increased activity for at least one LEF1/TCF-site in the Notch2 promoter upon co-transfection of HT29 or HCT116 cells with mutated b-catenin. HT29 cell lines were also treated with the g-secretase inhibitor DAPT, leading to inactivation of the Notch pathway by preventing release of NICD. However, results showed no effects on Apc, b-catenin or their target cyclin D1. Taken together, these results indicate that the Wnt pathway may function as a regulator of the Notch pathway through the TCF/LEF1 target gene program in colon cancer cell lines.

In summary, Notch pathway deregulation is of importance in both murine T-cell lymphoma and human colorectal cancer, although the mechanisms differ. The current results give new insights in Notch pathway alterations as well as the signalling networks in which the Notch pathway interacts, and thus increase the understanding of Notch’s involvement in malignant diseases.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. 52 p.
Series
Linköping Studies in Health Sciences. Thesis, ISSN 1100-6013 ; 106
Keyword
Notch signalling, T-cell lymphoma, colorectal cancer, Wnt signalling, transcription
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-51692 (URN)978-91-7393-510-4 (ISBN)
Presentation
2009-11-12, Conrad, Universitetssjukhuset, Campus US, Linköpings Universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Projects
Studies on molecular genetic alterations in colorectal cancer
Available from: 2009-11-19 Created: 2009-11-13 Last updated: 2009-11-19Bibliographically approved

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Karlsson, AnneliUngerbäck, JonasSöderkvist, Peter

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