ALK positively regulates MYCN activity through repression of HBP1 expression

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • Shana Claeys
  • Geertrui Denecker
  • Kaat Durinck
  • Bieke Decaesteker
  • Liselot M. Mus
  • Siebe Loontiens
  • Suzanne Vanhauwaert
  • Kristina Althoff
  • Caroline Wigerup
  • 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 Wilde
  • Olivier De Wever
  • Frank Westermann
  • Rogier Versteeg
  • Jan J. Molenaar
  • Johannes H. Schulte
  • Katleen De Preter
  • Frank Speleman
Enheter & grupper
Externa organisationer
  • Ghent University Hospital
  • Ghent University
  • University Hospital Essen
  • German Cancer Research Centre
  • Academic Medical Center
  • Princess Maxima Center for Pediatric Oncology/Hematology
  • Université catholique de Louvain
  • Charité Universitätsmedizin Berlin
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cancer och onkologi
Originalspråkengelska
Sidor (från-till)2690-2705
TidskriftOncogene
Volym38
Utgivningsnummer15
Tidigt onlinedatum2018
StatusPublished - 2019
PublikationskategoriForskning
Peer review utfördJa