title: Loss of function tp53 mutations do not accelerate the onset of myc-induced T-cell acute lymphoblastic leukaemia in the zebrafish.
abstract: The TP53 tumour suppressor is activated in response to distinct stimuli, including an ARF-dependent response to oncogene stress and an ATM/ATR-dependent response to DNA damage. In human T-cell acute lymphoblastic leukaemia (T-ALL), TP53-dependent tumour suppression is typically disabled via biallelic ARF deletions. In murine models, loss of Arf (Cdkn2a) or Tp53 markedly accelerates the onset of Myc-induced lymphoblastic malignancies. In zebrafish, no ARF ortholog has been identified, but the sequence of ARF is very poorly conserved evolutionarily, making it difficult to exclude the presence of a zebrafish ARF ortholog without functional studies. Here we show that tp53 mutations have no significant influence on the onset of myc-induced T-ALL in zebrafish, consistent with the lack of additional effects of Tp53 loss on lymphomagenesis in Arf-deficient mice. By contrast, irradiation leads to complete T-ALL regression in tp53 wild-type but not homozygous mutant zebrafish, indicating that the tp53-dependent DNA damage response is intact. We conclude that tp53 inactivation has no impact on the onset of myc-induced T-ALL in the zebrafish, consistent with the lack of a functional ARF ortholog linking myc-induced oncogene stress to tp53-dependent tumour suppression. Thus, the zebrafish model is well suited to the study of ARF-independent pathways in T-ALL pathobiology.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Gutierrez
authors.forename: Hui
authors.initials: H
authors.lastname: Feng
authors.forename: Kristen
authors.initials: K
authors.lastname: Stevenson
authors.forename: Donna S
authors.initials: DS
authors.lastname: Neuberg
authors.forename: Oscar
authors.initials: O
authors.lastname: Calzada
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.forename: David M
authors.initials: DM
authors.lastname: Langenau
authors.forename: A Thomas
authors.initials: AT
authors.lastname: Look
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004249:DNA Damage; D019143:Evolution, Molecular; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D009154:Mutation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D013045:Species Specificity; D060168:Thymocytes / Q000502:physiology / Q000528:radiation effects; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics; D015027:Zebrafish / Q000235:genetics*
chemical_list: D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016271:Proto-Oncogene Proteins c-myc; D025803:Tumor Suppressor Protein p14ARF
keywords: ARF; Myc; T-cell acute lymphoblastic leukaemia; Tp53; tumour suppression