Poster Presentation Advances in Neuroblastoma Research Congress 2016

Boolean modeling identifies Greatwall/MASTL as an important regulator in the AURKA network of neuroblastoma (#341)

Meike Dahlhaus 1 , Andre Burkovski 2 3 , Falk Hertwig 4 5 , Carmen Dorneburg 1 , Christoph Mussel 2 , Ruth Volland 4 , Matthias Fischer 4 5 , Klaus-Michael Debatin 1 , Hans A. Kestler 2 6 , Christian Beltinger 1
  1. Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
  2. Medical Systems Biology, Ulm University, Ulm, Germany
  3. International Graduate School of Molecular Medicine, Ulm University, Ulm, Germany
  4. Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Cologne, Germany
  5. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
  6. Leibniz Institute on Aging, Fritz-Lipmann Institute, Jena, Germany

Aurora Kinase A (AURKA) is often overexpressed in neuroblastoma (NB) with poor outcome. The causes of AURKA overexpression in NB are unknown. Here, we describe a gene regulatory network consisting of core regulators of AURKA protein expression and activation during mitosis to identify potential causes. This network was transformed to a dynamic Boolean model. Simulated activation of the serine/threonine protein kinase Greatwall (GWL, encoded by MASTL) that attenuates the pivotal AURKA inhibitor PP2A, predicted stabilization of AURKA. Consistent with this notion, gene set enrichment analysis showed enrichment of mitotic spindle assembly genes and MYCN target genes in NB with high GWL/MASTL expression. In line with the prediction of GWL/MASTL enhancing AURKA, elevated expression of GWL/MASTL was associated with NB risk factors and poor survival of patients. These results establish Boolean network modeling of oncogenic pathways in NB as a useful means for guided discovering in this enigmatic cancer.