title: Synergy between loss of NF1 and overexpression of MYCN in neuroblastoma is mediated by the GAP-related domain.
abstract: Earlier reports showed that hyperplasia of sympathoadrenal cell precursors during embryogenesis in Nf1-deficient mice is independent of Nf1's role in down-modulating RAS-MAPK signaling. We demonstrate in zebrafish that nf1 loss leads to aberrant activation of RAS signaling in MYCN-induced neuroblastomas that arise in these precursors, and that the GTPase-activating protein (GAP)-related domain (GRD) is sufficient to suppress the acceleration of neuroblastoma in nf1-deficient fish, but not the hypertrophy of sympathoadrenal cells in nf1 mutant embryos. Thus, even though neuroblastoma is a classical "developmental tumor", NF1 relies on a very different mechanism to suppress malignant transformation than it does to modulate normal neural crest cell growth. We also show marked synergy in tumor cell killing between MEK inhibitors (trametinib) and retinoids (isotretinoin) in primary nf1a-/- zebrafish neuroblastomas. Thus, our model system has considerable translational potential for investigating new strategies to improve the treatment of very high-risk neuroblastomas with aberrant RAS-MAPK activation.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States.
authors.forename: Shuning
authors.initials: S
authors.lastname: He
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States.|Department of Hematology, UCL Cancer Institute, University College London, London, United Kingdom.
authors.forename: Marc R
authors.initials: MR
authors.lastname: Mansour
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Zimmerman
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States.
authors.forename: Dong Hyuk
authors.initials: DH
authors.lastname: Ki
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States.
authors.forename: Hillary M
authors.initials: HM
authors.lastname: Layden
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States.
authors.forename: Koshi
authors.initials: K
authors.lastname: Akahane
authors.affiliation: Center for Immuno-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States.
authors.forename: Evisa
authors.initials: E
authors.lastname: Gjini
authors.affiliation: Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States.|Penn Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States.|Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States.
authors.forename: Eric D
authors.initials: ED
authors.lastname: de Groh
authors.affiliation: Department of Pathology, Children's Hospital Boston, Harvard Medical School, Boston, United States.
authors.forename: Antonio R
authors.initials: AR
authors.lastname: Perez-Atayde
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States.|Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, United States.|Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, United States.
authors.forename: Shizhen
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States.|Penn Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States.|Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Epstein
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States.
authors.forename: A Thomas
authors.identifier: 0000-0001-7851-8617
authors.initials: AT
authors.lastname: Look
mesh_terms: D000818:Animals; D015870:Gene Expression; D000071447:N-Myc Proto-Oncogene Protein / Q000096:biosynthesis*; D058953:Neural Stem Cells / Q000502:physiology*; D009447:Neuroblastoma / Q000473:pathology*; D025542:Neurofibromin 1 / Q000172:deficiency*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D015398:Signal Transduction; D015027:Zebrafish
chemical_list: D000071447:N-Myc Proto-Oncogene Protein; D025542:Neurofibromin 1; D016283:Proto-Oncogene Proteins p21(ras)
keywords: cancer biology; neuroblastoma; nf1; peripheral sympathetic nervous system; zebrafish