1. Loss of functiontp53mutations do not accelerate the onset ofmyc-induced T-cell acute lymphoblastic leukaemia in the zebrafish
- Author
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Kristen E. Stevenson, Oscar Calzada, A. Thomas Look, Yi Zhou, Alejandro Gutierrez, Donna Neuberg, David M. Langenau, and Hui Feng
- Subjects
endocrine system diseases ,DNA damage ,Mutant ,Apoptosis ,Kaplan-Meier Estimate ,Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease_cause ,Article ,law.invention ,Animals, Genetically Modified ,Evolution, Molecular ,Proto-Oncogene Proteins c-myc ,Species Specificity ,CDKN2A ,law ,Tumor Suppressor Protein p14ARF ,medicine ,Animals ,Humans ,neoplasms ,Zebrafish ,Cyclin-Dependent Kinase Inhibitor p16 ,Loss function ,Cyclin-Dependent Kinase Inhibitor p15 ,Mutation ,Thymocytes ,Oncogene ,biology ,Hematology ,Genes, p53 ,biology.organism_classification ,Cell Transformation, Neoplastic ,Cancer research ,Suppressor ,DNA Damage - 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.
- Published
- 2014