Loss of function tp53 mutations do not accelerate the onset of myc‐induced T‐cell acute lymphoblastic leukaemia in the zebrafish

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.