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- W2319173628 abstract "The discovery of activating mutations in the ALK gene in primary neuroblastomas (NB) opened new opportunities to treat children with these tumors. Clinical trials for small molecule ALK inhibitors show that tumors acquire resistance to these inhibitors. This illustrates the need for additional compounds targeting downstream genes or alternative pathways. In order to identify new vulnerable nodes for targeted (and combinatorial) therapy, we aimed at deciphering downstream ALK signaling through expression profiling of a panel of 10 NB cell lines (ALK wild type, ALKF1174L, ALKR1275Q mutant or amplified) treated with ALK inhibitor NVP-TAE684.In depth data-mining lead to the identification of a 79-gene signature that recapitulates the transcriptional response upon ALK inhibition. Functional annotation analysis clearly showed that this signature is mainly composed of genes involved in MAPK/ERK, PI3K/AKT/mTOR, MYC/MYCN and neuronal differentiation signaling. Most interestingly iRegulon analysis (http://iregulon.aertslab.org) pinpointed transcription repressor HBP1 as a hub gene that acts downstream of ALK.In previous studies it is described that also MYC(N) regulates HBP1, and that it probably acts through repression by downstream miR-17-92. Indeed, we could confirm HBP1 repression by miR-17-92 in a neuroblastoma cell line with inducible miR-17-92 (SHEP-miR-17-92). Furthermore, in vitro studies in NB cell lines with stable HBP1 overexpression demonstrated reduction of cell growth and increase of cell death. Most interestingly, we identified a green tea component EGCG that can up-regulate HBP1 expression in cell lines and that lead to cell death.In conclusion, this study unraveled the transcriptional consequences of aberrant ALK signaling in human NB cell lines. Moreover, we identified HBP1 as a targetable component of ALK downstream signaling." @default.
- W2319173628 created "2016-06-24" @default.
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- W2319173628 date "2014-01-01" @default.
- W2319173628 modified "2023-09-27" @default.
- W2319173628 title "Green tea compound EGCG activates HBP1: an ALK downstream suppressor gene in neuroblastoma" @default.
- W2319173628 hasPublicationYear "2014" @default.
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