The tumor suppressor CREBBP and the oncogene MYCN cooperate to induce malignant brain tumors in mice

Melanie Schoof; Gefion Dorothea Epplen; Carolin Walter; Annika Ballast; Dörthe Holdhof; Carolin Göbel; Sina Neyazi; Julian Varghese; Thomas Karl Albert; Kornelius Kerl; Ulrich Schüller

doi:10.1038/s41389-023-00481-3

The tumor suppressor CREBBP and the oncogene MYCN cooperate to induce malignant brain tumors in mice

Oncogenesis. 2023 Jul 5;12(1):36. doi: 10.1038/s41389-023-00481-3.

Authors

Melanie Schoof^#^{1

2}, Gefion Dorothea Epplen^#¹, Carolin Walter³, Annika Ballast⁴, Dörthe Holdhof^{1

2}, Carolin Göbel^{1

2}, Sina Neyazi^{1

2}, Julian Varghese³, Thomas Karl Albert⁴, Kornelius Kerl⁴, Ulrich Schüller^{5

6

7}

Affiliations

¹ Research Institute Children`s Cancer Center, Hamburg, Germany.
² Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
³ Institute of Medical Informatics, University of Münster, Münster, Germany.
⁴ Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, Münster, Germany.
⁵ Research Institute Children`s Cancer Center, Hamburg, Germany. u.schueller@uke.de.
⁶ Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. u.schueller@uke.de.
⁷ Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. u.schueller@uke.de.

^# Contributed equally.

Abstract

The tumor suppressor and chromatin modifier cAMP response element-binding protein binding protein (CREBBP) and v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN), a member of the MYC oncogene family, are critically involved in brain development. Both genes are frequently mutated in the same tumor entities, including high-grade glioma and medulloblastoma. Therefore, we hypothesized that alterations in both genes cooperate to induce brain tumor formation. For further investigation, hGFAP-cre::Crebbp^Fl/Fl::lsl-MYCN mice were generated, which combine Crebbp deletion with overexpression of MYCN in neural stem cells (NSCs). Within eight months, these animals developed aggressive forebrain tumors. The first tumors were detectable in the olfactory bulbs of seven-day-old mice. This location raises the possibility that presumptive founder cells are derived from the ventricular-subventricular zone (V-SVZ). To examine the cellular biology of these tumors, single-cell RNA sequencing was performed, which revealed high intratumoral heterogeneity. Data comparison with reference CNS cell types indicated the highest similarity of tumor cells with transit-amplifying NSCs or activated NSCs of the V-SVZ. Consequently, we analyzed V-SVZ NSCs of our mouse model aiming to confirm that the tumors originate from this stem cell niche. Mutant V-SVZ NSCs showed significantly increased cell viability and proliferation as well as reduced glial and neural differentiation in vitro compared to control cells. In summary, we demonstrate the oncogenic potential of a combined loss of function of CREBBP and overexpression of MYCN in this cell population. hGFAP-cre::Crebbp^Fl/Fl::lsl-MYCN mice thus provide a valuable tool to study tumor-driving mechanisms in a key neural stem/ progenitor cell niche.