EIF4EBP1 is transcriptionally upregulated by MYCN and associates with poor prognosis in neuroblastoma

Kai Voeltzke; Katerina Scharov; Cornelius Maximilian Funk; Alisa Kahler; Daniel Picard; Laura Hauffe; Martin F Orth; Marc Remke; Irene Esposito; Thomas Kirchner; Alexander Schramm; Barak Rotblat; Thomas G P Grünewald; Guido Reifenberger; Gabriel Leprivier

doi:10.1038/s41420-022-00963-0

EIF4EBP1 is transcriptionally upregulated by MYCN and associates with poor prognosis in neuroblastoma

Cell Death Discov. 2022 Apr 4;8(1):157. doi: 10.1038/s41420-022-00963-0.

Authors

Kai Voeltzke¹, Katerina Scharov^{1

2}, Cornelius Maximilian Funk^{3

4

5}, Alisa Kahler¹, Daniel Picard^{1

2

6}, Laura Hauffe¹, Martin F Orth³, Marc Remke^{1

2

6}, Irene Esposito⁷, Thomas Kirchner^{8

9}, Alexander Schramm¹⁰, Barak Rotblat^{11

12}, Thomas G P Grünewald^{3

4

5

13}, Guido Reifenberger^{1

6}, Gabriel Leprivier¹⁴

Affiliations

¹ Institute of Neuropathology, University Hospital Düsseldorf, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
² Department of Pediatric Oncology, Hematology, and Clinical Immunology, University Hospital Düsseldorf, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
³ Faculty of Medicine, Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, LMU Munich, Munich, Germany.
⁴ Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁵ Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
⁶ German cancer consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany.
⁷ Institute of Pathology, Heinrich Heine University, Medical Faculty, and University Hospital Düsseldorf, Düsseldorf, Germany.
⁸ Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
⁹ German cancer consortium (DKTK) partner site Munich, Munich, Germany.
¹⁰ Department of Medical Oncology, West German Cancer Center, University of Duisburg-Essen, Essen, Germany.
¹¹ Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.
¹² The National Institute for Biotechnology in the Negev, Beer Sheva, Israel.
¹³ Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
¹⁴ Institute of Neuropathology, University Hospital Düsseldorf, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany. gabriel.leprivier@med.uni-duesseldorf.de.

Abstract

Neuroblastoma (NB) accounts for 15% of cancer-related deaths in childhood despite considerable therapeutic improvements. While several risk factors, including MYCN amplification and alterations in RAS and p53 pathway genes, have been defined in NB, the clinical outcome is very variable and difficult to predict. Since genes of the mechanistic target of rapamycin (mTOR) pathway are upregulated in MYCN-amplified NB, we aimed to define the predictive value of the mTOR substrate-encoding gene eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1) expression in NB patients. Using publicly available data sets, we found that EIF4EBP1 mRNA expression is positively correlated with MYCN expression and elevated in stage 4 and high-risk NB patients. In addition, high EIF4EBP1 mRNA expression is associated with reduced overall and event-free survival in the entire group of NB patients in three cohorts, as well as in stage 4 and high-risk patients. This was confirmed by monitoring the clinical value of 4EBP1 protein expression, which revealed that high levels of 4EBP1 are significantly associated with prognostically unfavorable NB histology. Finally, functional analyses revealed that EIF4EBP1 expression is transcriptionally controlled by MYCN binding to the EIF4EBP1 promoter in NB cells. Our data highlight that EIF4EBP1 is a direct transcriptional target of MYCN whose high expression is associated with poor prognosis in NB patients. Therefore, EIF4EBP1 may serve to better stratify patients with NB.