Loss of function tp53 mutations do not accelerate the onset of myc‐induced T‐cell acute lymphoblastic leukaemia in the zebrafish. (2nd April 2014)

• Record Type: Journal Article
• Authors: Gutierrez, Alejandro; Feng, Hui; Stevenson, Kristen; Neuberg, Donna S.; Calzada, Oscar; Zhou, Yi; Langenau, David M.; Look, A. Thomas
• Is Part Of: British journal of haematology. Volume 166:Number 1(2014:Jul.)
• Page Start: 84
• Page End: 90
• Publication Date: 2014-04-02
• Subjects: Hematology -- Periodicals; Blood -- Diseases -- Periodicals; 616.15
• DOI: 10.1111/bjh.12851
• Languages: English
• ISSNs: 0007-1048

Abstract

<abstract abstract-type="main" id="bjh12851-abs-0001"> <title>Summary</title> <p>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), <italic>TP53</italic>‐dependent tumour suppression is typically disabled via biallelic ARF deletions. In murine models, loss of <italic>Arf</italic> (<italic>Cdkn2a</italic>) or <italic>Tp53</italic> markedly accelerates the onset of <italic>Myc</italic>‐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 <italic>tp53</italic> mutations have no significant influence on the onset of <italic>myc</italic>‐induced T‐ALL in zebrafish, consistent with the lack of additional effects of <italic>Tp53</italic> loss on lymphomagenesis in <italic>Arf</italic>‐deficient mice. By contrast, irradiation leads to complete T‐ALL regression in <italic>tp53</italic> wild‐type but not homozygous mutant zebrafish, indicating that the <italic>tp53</italic>‐dependent DNA damage response is intact. We conclude that <italic>tp53</italic> inactivation has no impact on the onset of <italic>myc</italic>‐induced T‐ALL in the zebrafish, consistent with the lack of a functional ARF ortholog linking <italic>myc</italic>‐induced oncogene stress to <italic>tp53</italic>‐dependent tumour suppression. Thus, the zebrafish model is well suited to the study of ARF‐independent pathways in T‐ALL pathobiology.</p> </abstract>