ZFIN ID: ZDB-PUB-140513-232
Loss of function tp53 mutations do not accelerate the onset of myc-induced T-cell acute lymphoblastic leukaemia in the zebrafish
Gutierrez, A., Feng, H., Stevenson, K., Neuberg, D.S., Calzada, O., Zhou, Y., Langenau, D.M., Look, A.T.
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 (all 20) expand
PubMed: 24690081 Full text @ Br. J. Haematol.
FIGURES   (current status)
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.