title: NF1 is a tumor suppressor in neuroblastoma that determines retinoic acid response and disease outcome.
abstract: Retinoic acid (RA) induces differentiation of neuroblastoma cells in vitro and is used with variable success to treat aggressive forms of this disease. This variability in clinical response to RA is enigmatic, as no mutations in components of the RA signaling cascade have been found. Using a large-scale RNAi genetic screen, we identify crosstalk between the tumor suppressor NF1 and retinoic acid-induced differentiation in neuroblastoma. Loss of NF1 activates RAS-MEK signaling, which in turn represses ZNF423, a critical transcriptional coactivator of the retinoic acid receptors. Neuroblastomas with low levels of both NF1 and ZNF423 have extremely poor outcome. We find NF1 mutations in neuroblastoma cell lines and in primary tumors. Inhibition of MEK signaling downstream of NF1 restores responsiveness to RA, suggesting a therapeutic strategy to overcome RA resistance in NF1-deficient neuroblastomas.
authors.affiliation: Divisions of Molecular Carcinogenesis and Molecular Genetics, Center for Biomedical Genetics and Cancer Genomics Center, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Michael
authors.initials: M
authors.lastname: Hölzel
authors.forename: Sidong
authors.initials: S
authors.lastname: Huang
authors.forename: Jan
authors.initials: J
authors.lastname: Koster
authors.forename: Ingrid
authors.initials: I
authors.lastname: Ora
authors.forename: Arjan
authors.initials: A
authors.lastname: Lakeman
authors.forename: Huib
authors.initials: H
authors.lastname: Caron
authors.forename: Wouter
authors.initials: W
authors.lastname: Nijkamp
authors.forename: Jing
authors.initials: J
authors.lastname: Xie
authors.forename: Tom
authors.initials: T
authors.lastname: Callens
authors.forename: Shahab
authors.initials: S
authors.lastname: Asgharzadeh
authors.forename: Robert C
authors.initials: RC
authors.lastname: Seeger
authors.forename: Ludwine
authors.initials: L
authors.lastname: Messiaen
authors.forename: Rogier
authors.initials: R
authors.lastname: Versteeg
authors.forename: René
authors.initials: R
authors.lastname: Bernards
mesh_terms: D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D009447:Neuroblastoma / Q000175:diagnosis* / Q000378:metabolism; D025542:Neurofibromin 1 / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D011506:Proteins; D015398:Signal Transduction; D015533:Transcriptional Activation; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D025542:Neurofibromin 1; D011506:Proteins; C031017:ornithine decarboxylase antizyme; D014212:Tretinoin