Loss of function tp53 mutations do not accelerate the onset of myc-induced T-cell acute lymphoblastic leukaemia in the zebrafish.
Br J Haematol
; 166(1): 84-90, 2014 Jul.
Article
en En
| MEDLINE
| ID: mdl-24690081
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Pez Cebra
/
Genes p53
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Proteínas Proto-Oncogénicas c-myc
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Leucemia-Linfoma Linfoblástico de Células T Precursoras
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Mutación
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Br J Haematol
Año:
2014
Tipo del documento:
Article
País de afiliación:
Estados Unidos