| 1. |
- Chand, Damini, 1986, et al.
(författare)
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Cell culture and Drosophila model systems define three classes of anaplastic lymphoma kinase mutations in neuroblastoma.
- 2013
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Ingår i: Disease models & mechanisms. - Cambridge, UK : The Company of Biologists. - 1754-8411 .- 1754-8403. ; 6:2, s. 373-82
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Tidskriftsartikel (refereegranskat)abstract
- Neuroblastoma is a childhood extracranial solid tumor which is associated with a number of genetic changes. Included in these genetic alterations are mutations in the kinase domain of the Anaplastic Lymphoma Kinase (ALK) receptor tyrosine kinase (RTK), which have been found in both somatic and familial neuroblastoma. In order to treat patients accordingly required characterisation of these mutations in terms of their response to ALK tyrosine kinase inhibitors (TKIs). Here, we report the identification and characterisation of two novel neuroblastoma ALK mutations (A1099T and 1464STOP) which we have investigated together with several previously reported but uncharacterised ALK mutations (T1087I, D1091N, T1151M, M1166R, F1174I and A1234T). In order to understand the potential role of these ALK mutations in neuroblastoma progression we have employed cell culture based systems together with the model organism Drosophila as a readout for ligand-independent activity. Mutation of ALK at position F1174I generates a gain-of-function receptor capable of activating intracellular targets, such as ERK (extracellular signal regulated kinase) and STAT3 (signal transducer and activator of transcription 3) in a ligand independent manner. Analysis of these previously uncharacterised ALK mutants and comparison with ALK(F1174) mutants suggests that ALK mutations observed in neuroblastoma fall into three classes. These are: (i) gain-of-function ligand independent mutations such as ALK(F1174), (ii) kinase-dead ALK mutants, e.g. ALK(I1250T)(Schonherr et al 2011a) or (iii) ALK mutations which are ligand-dependent in nature. Irrespective of the nature of the observed ALK mutants, in every case the activity of the mutant ALK receptors could be abrogated by the ALK inhibitor crizotinib (PF-02341066, Xalkori), albeit with differing levels of sensitivity.
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| 2. |
- De Brouwer, Sara, et al.
(författare)
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Meta-analysis of neuroblastomas reveals a skewed ALK mutation spectrum in tumors with MYCN amplification.
- 2010
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Ingår i: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1078-0432 .- 1557-3265. ; 16:17, s. 4353-62
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Tidskriftsartikel (refereegranskat)abstract
- Activating mutations of the anaplastic lymphoma kinase (ALK) were recently described in neuroblastoma. We carried out a meta-analysis of 709 neuroblastoma tumors to determine their frequency and mutation spectrum in relation to genomic and clinical parameters, and studied the prognostic significance of ALK copy number and expression.
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| 3. |
- Wetterskog, Daniel, 1978, et al.
(författare)
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Dysregulation of platelet-derived growth factor beta-receptor expression by DeltaNp73 in neuroblastoma
- 2009
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Ingår i: Molecular Cancer Research. - 1541-7786. ; 7:12, s. 2031-2039
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Tidskriftsartikel (refereegranskat)abstract
- We have previously characterized how p53 family proteins control the transcriptional regulation of the platelet-derived growth factor beta-receptor (PDGFRB) and found that DeltaNp73alpha, acting dominant-negatively to p53 and p73, can upregulate PDGFRB promoter activity. Here, we report that PDGFRB regulation differs between two neuroblastoma cell lines, correlating with the actions of DeltaNp73. We found that PDGFRB was highly expressed in IMR-32 cells, and serum stimulation of IMR-32 cells did not downregulate PDGFRB expression, as seen in SH-SY5Y cells. In IMR-32, DeltaNp73 was found constitutively bound to the PDGFRB promoter, and silencing of DeltaNp73 resulted in repression of PDGFRB promoter activity as well as decreased PDGFRB protein expression. However, the anticancer drug cisplatin, known to stabilize and activate p53 and p73, downregulated PDGFRB expression not only in SH-SY5Y but also in IMR-32. Chromatin immunoprecipitation showed that cisplatin removed DeltaNp73 from the PDGFRB promoter and recruited p53 and p73, leading to binding of histone deacetylase 4. These results suggest a direct role of DeltaNp73 in the constantly enhanced PDGFRB expression seen in tumors.
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