ALK positively regulates MYCN activity through repression of HBP1 expression

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Shana Claeys1,2, Geertrui Denecker1,2, Kaat Durinck1,2

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

Oncogene
|December 13, 2018
PubMed

Insights

Mutant anaplastic lymphoma kinase (ALK) signaling in neuroblastoma downregulates HMG-box transcription factor 1 (HBP1). Targeting HBP1 and MYCN offers a novel therapeutic strategy for high-risk pediatric tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pediatric Cancer Research

Background:

  • Anaplastic lymphoma kinase (ALK) mutations are found in 10% of neuroblastomas, often associated with MYCN amplification, indicating an ultra-high-risk phenotype and poor prognosis.
  • Understanding the molecular mechanisms of constitutive ALK signaling and its interplay with MYCN is crucial for developing precision therapies for aggressive pediatric neuroblastoma.

Purpose of the Study:

  • To elucidate the molecular consequences of mutant ALK signaling in neuroblastoma.
  • To investigate the relationship between ALK signaling, MYCN activity, and the HMG-box transcription factor 1 (HBP1) in high-risk neuroblastoma.

Main Methods:

  • Investigated the role of the PI3K-AKT-FOXO3a signaling axis in mediating ALK's effect on HBP1.
  • Assessed the inhibitory effects of HBP1 on both transcriptional activation and repression by MYCN, including MYCN-mediated PRC2 activity.
  • Examined the negative regulation of HBP1 by MYCN via the miR-17~92 cluster.

Main Results:

  • Mutant ALK signaling was found to downregulate HBP1 expression through the PI3K-AKT-FOXO3a pathway.
  • HBP1 inhibits both activating and repressing functions of MYCN, with repression mediated by PRC2.
  • MYCN negatively regulates HBP1 through the miR-17~92 microRNA cluster.

Conclusions:

  • Combined inhibition of HBP1 using PI3K antagonists and MYCN signaling via BET or HDAC inhibitors effectively blocks MYCN activity.
  • This combined therapeutic approach significantly reduces tumor growth in preclinical models.
  • Suggests a novel targeted therapy strategy for high-risk neuroblastoma patients with ALK mutations and MYCN amplification.

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