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ALK positively regulates MYCN activity through repression of HBP1 expression

Oncogene volume 38, pages 2690–2705 (2019)Cite this article

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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.

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Acknowledgements

We thank Jeroen Schacht, Jolien Van Laere, Els De Smet, Fanny De Vloed, Givani Dewyn, and Aline Eggermont from our lab as well as Glenn Wagemans from the LECR for their outstanding technical assistance. Furthermore, we thank Els Janssens, Annelies Fieuw, Sara De Brouwer, and Irina Lambertz for their guidance during this project.

Funding

S.C. is supported by a pre-doctoral fellowship of the Research Foundation—Flanders (FWO; 11J8313N) and an Emmanuel van der Schueren grant (‘Kom op tegen Kanker’). S.V. is funded by the VLK (Flemish League against cancer) and ‘Stichting Villa Joep’. B.D. and S.L. are supported by a pre-doctoral fellowship of the FWO Research Foundation—Flanders (FWO). K.D. is supported by Ghent University (BOF; BOF16/PDO/043). C.V., B.D.W. and T.V.M. are senior clinical investigators of the Research Foundation—Flanders (FWO; 18B1716N (B.D.W.), 12N6917N (C.V.), 1803115 N (T.V.M.)). We would further like to thank the following funding agencies: the Belgian Foundation against Cancer (project 2014–175) to F.S., Ghent University (BOF10/GOA/019, BOF16/GOA/23) to F.S., the Belgian Program of Interuniversity Poles of Attraction (IUAP Phase VII–P7/03) to F.S., the fund for Scientific Research Flanders (Research projects G053012N, G050712N, G051516N to F.S) and ‘Stichting Villa Joep’ to F.S.

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  1. These authors contributed equally: Kaat Durinck, Bieke Decaesteker

Authors and Affiliations

  1. Center for Medical Genetics Ghent (CMGG), Ghent University, Ghent, Belgium

    Shana Claeys, Geertrui Denecker, Kaat Durinck, Bieke Decaesteker, Liselot M. Mus, Siebe Loontiens, Suzanne Vanhauwaert, Candy Kumps, Tom Van Maerken, Christophe Van Neste, Bram De Wilde, Katleen De Preter & Frank Speleman

  2. Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium

    Shana Claeys, Geertrui Denecker, Kaat Durinck, Bieke Decaesteker, Liselot M. Mus, Siebe Loontiens, Suzanne Vanhauwaert, Tom Van Maerken, Genevieve Laureys, Christophe Van Neste, Bram De Wilde, Olivier De Wever, Katleen De Preter & Frank Speleman

  3. Department of Pediatric Oncology and Hematology, University Children’s Hospital Essen, Essen, Germany

    Kristina Althoff

  4. Translational Cancer Research, Lund University Cancer Center at Medicon Village, Lund University, Lund, Sweden

    Caroline Wigerup, Daniel Bexell & Sven Påhlman

  5. Princess Maxima Center for Pediatric Cancer, Utrecht, The Netherlands

    Emmy Dolman & Jan J. Molenaar

  6. Neuroblastoma Genomics B087, German Cancer Research Center, Heidelberg, Germany

    Kai-Oliver Henrich, Lea Wehrmann & Frank Westermann

  7. Department of Oncogenomics, Academic Medical Center, Amsterdam, The Netherlands

    Ellen M. Westerhout & Rogier Versteeg

  8. De Duve Institute, Université Catholique de Louvain, Brussels, Belgium

    Jean-Baptiste Demoulin

  9. Department of Uro-Gynaecology, Ghent University Hospital, Ghent, Belgium

    Candy Kumps

  10. Department of Pediatric Oncology and Hematology, Ghent University Hospital, Ghent, Belgium

    Genevieve Laureys & Bram De Wilde

  11. Laboratory of Experimental Cancer Research (LECR), Ghent University, Ghent, Belgium

    Olivier De Wever

  12. Department of Pediatric Oncology/Hematology, Charite University Hospital Berlin, Berlin, Germany

    Johannes H. Schulte

  13. Berlin Institute of Health (BIH), Berlin, Germany

    Johannes H. Schulte

  14. German Translational Cancer Research Consortium (DKTK), Berlin, Germany

    Johannes H. Schulte

  15. German Translational Cancer Research Consortium (DKFZ), Heidelberg, Germany

    Johannes H. Schulte

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Correspondence to Frank Speleman.

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Claeys, S., Denecker, G., Durinck, K. et al. ALK positively regulates MYCN activity through repression of HBP1 expression. Oncogene 38, 2690–2705 (2019). https://doi.org/10.1038/s41388-018-0595-3

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