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- Title
Loss of function tp53 mutations do not accelerate the onset of myc-induced T-cell acute lymphoblastic leukaemia in the zebrafish.
- Authors
Gutierrez, Alejandro; Feng, Hui; Stevenson, Kristen; Neuberg, Donna S.; Calzada, Oscar; Zhou, Yi; Langenau, David M.; Look, A. Thomas
- 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.
- Subjects
TUMOR proteins; P53 protein; TUMOR suppressor genes; MYC oncogenes; T-cell lymphoma; DNA damage; LABORATORY zebrafish
- Publication
British Journal of Haematology, 2014, Vol 166, Issue 1, p84
- ISSN
0007-1048
- Publication type
Article
- DOI
10.1111/bjh.12851