ALK positively regulates MYCN activity through repression of HBP1 expression

Shana Claeys, Geertrui Denecker, Kaat Durinck, Bieke Decaesteker, Liselot M. Mus, Siebe Loontiens, Suzanne Vanhauwaert, Kristina Althoff, Caroline Wigerup, Daniel Bexell, Emmy Dolman, Kai Oliver Henrich, Lea Wehrmann, Ellen M. Westerhout, Jean Baptiste Demoulin, Candy Kumps, Tom Van Maerken, Genevieve Laureys, Christophe Van Neste, Bram De WildeOlivier De Wever, Frank Westermann, Rogier Versteeg, Jan J. Molenaar, Sven Påhlman, Johannes H. Schulte, Katleen De Preter, Frank Speleman

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

9 Citaten (Scopus)

Samenvatting

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 PI 3 K-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 PI 3 K 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.

Originele taal-2Engels
Pagina's (van-tot)2690-2705
Aantal pagina's16
TijdschriftOncogene
Volume38
Nummer van het tijdschrift15
DOI's
StatusGepubliceerd - 11 apr. 2019

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