| Literature DB >> 30538293 |
Shana Claeys1,2, Geertrui Denecker1,2, Kaat Durinck1,2, Bieke Decaesteker1,2, Liselot M Mus1,2, Siebe Loontiens1,2, Suzanne Vanhauwaert1,2, Kristina Althoff3, Caroline Wigerup4, Daniel Bexell4, Emmy Dolman5, Kai-Oliver Henrich6, Lea Wehrmann6, Ellen M Westerhout7, Jean-Baptiste Demoulin8, Candy Kumps1,9, Tom Van Maerken1,2, Genevieve Laureys2,10, Christophe Van Neste1,2, Bram De Wilde1,2,10, Olivier De Wever2,11, Frank Westermann6, Rogier Versteeg7, Jan J Molenaar5, Sven Påhlman4, Johannes H Schulte12,13,14,15, Katleen De Preter1,2, Frank Speleman16,17.
Abstract
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-17~92. 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.Entities:
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Year: 2018 PMID： 30538293 DOI： 10.1038/s41388-018-0595-3
Source DB: PubMed Journal: Oncogene ISSN： 0950-9232 Impact factor: 9.867