期刊
ONCOGENE
卷 38, 期 15, 页码 2690-2705出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41388-018-0595-3
关键词
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资金
- Research Foundation-Flanders (FWO) [11J8313N, 18B1716N, 12N6917N, 1803115 N]
- Emmanuel van der Schueren grant ('Kom op tegen Kanker')
- VLK (Flemish League against cancer)
- FWO Research Foundation-Flanders (FWO)
- Ghent University (BOF) [BOF16/PDO/043]
- Belgian Foundation against Cancer [2014-175]
- Ghent University [BOF10/GOA/019, BOF16/GOA/23]
- Belgian Program of Interuniversity Poles of Attraction (IUAP) [VII-P7/03]
- fund for Scientific Research Flanders [G053012N, G050712N, G051516N]
- Stichting Villa Joep
ALK mutations occur in 10% of primary neuroblastomas and represent a major target for precision treatment. In combination with MYCN amplification, ALK mutations infer an ultra-high-risk phenotype resulting in very poor patient prognosis. To open up opportunities for future precision drugging, a deeper understanding of the molecular consequences of constitutive ALK signaling and its relationship to MYCN activity in this aggressive pediatric tumor entity will be essential. We show that mutant ALK downregulates the 'HMG-box transcription factor 1' (HBP1) through the PI3K-AKT-FOXO3a signaling axis. HBP1 inhibits both the transcriptional activating and repressing activity of MYCN, the latter being mediated through PRC2 activity. HBP1 itself is under negative control of MYCN through miR-17 similar to 92. Combined targeting of HBP1 by PI3K antagonists and MYCN signaling by BET- or HDAC-inhibitors blocks MYCN activity and significantly reduces tumor growth, suggesting a novel targeted therapy option for high-risk neuroblastoma.
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