Constitutive STAT5 activation specifically cooperates with the loss of p53 function in B-cell lymphomagenesis.
Signal transducers and activator of transcription 5 (STAT5) A and B are transcriptional regulators that play a central role in cytokine signaling in the hematopoietic lineage and which are frequently activated in a persistent manner in human leukemia/lymphoma, as assessed by their constitutive tyrosine phosphorylation and DNA-binding activity. To study the intrinsic oncogenic properties of persistent STAT5 activation, we generated transgenic mice in which a constitutively activated point mutant of STAT5A, STAT5A(S711F), was expressed at physiological level in their lymphoid compartment. In this model, persistent STAT5 activation is weakly oncogenic, leading to the late emergence of clonal B-cell lymphoma/leukemia at a low incidence. In contrast, STAT5(S711F) was found to cooperate with the loss of function of the p53 tumor suppressor gene to both accelerate disease onset and to skew the large tumor spectrum that normally characterize p53-deficient mice to strongly favor B-cell lymphoma/leukemia. The emergence of STAT5A(S711F)-induced B-cell tumors is associated with the activation of STAT5 tyrosine phosphorylation and DNA-binding activity, indicating that activation of STAT5 oncogenic properties in transgenic STAT5A (TgSTAT5A) (S711F) mice involves the deregulation of STAT5 phosphorylation dynamics.
Institut Curie, CNRS UMR146, Centre Universitaire, Orsay, France.
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V
Joliot
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F
Cormier
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H
Medyouf
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H
Alcalde
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Ghysdael
D000818:Animals; D019070:Cell Lineage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D008957:Models, Genetic; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D017354:Point Mutation; D011485:Protein Binding; D050799:STAT5 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D050799:STAT5 Transcription Factor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53