PUBLICATION
Loss of function tp53 mutations do not accelerate the onset of myc-induced T-cell acute lymphoblastic leukaemia in the zebrafish
- Authors
- Gutierrez, A., Feng, H., Stevenson, K., Neuberg, D.S., Calzada, O., Zhou, Y., Langenau, D.M., Look, A.T.
- ID
- ZDB-PUB-140513-232
- Date
- 2014
- Source
- British journal of haematology 166(1): 84-90 (Journal)
- Registered Authors
- Calzada, Oscar, Feng, Hui, Gutierrez, Alejandro, Langenau, David, Look, A. Thomas, Zhou, Yi
- Keywords
- ARF, Myc, T-cell acute lymphoblastic leukaemia, Tp53, tumour suppression
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Apoptosis/genetics
- Cell Transformation, Neoplastic/genetics
- Cyclin-Dependent Kinase Inhibitor p15/genetics
- Cyclin-Dependent Kinase Inhibitor p16/genetics
- DNA Damage
- Evolution, Molecular
- Genes, p53/genetics*
- Humans
- Kaplan-Meier Estimate
- Mutation*
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics*
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology
- Proto-Oncogene Proteins c-myc/genetics*
- Species Specificity
- Thymocytes/physiology
- Thymocytes/radiation effects
- Tumor Suppressor Protein p14ARF/genetics
- Zebrafish/genetics*
- PubMed
- 24690081 Full text @ Br. J. Haematol.
Citation
Gutierrez, A., Feng, H., Stevenson, K., Neuberg, D.S., Calzada, O., Zhou, Y., Langenau, D.M., Look, A.T. (2014) Loss of function tp53 mutations do not accelerate the onset of myc-induced T-cell acute lymphoblastic leukaemia in the zebrafish. British journal of haematology. 166(1):84-90.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping