<i>Fli-1</i> Overexpression in Hematopoietic Progenitors Deregulates T Cell Development and Induces Pre-T Cell Lymphoblastic Leukaemia/Lymphoma

<div><p>The <i>Ets</i> transcription factor <i>Fli-1</i> is preferentially expressed in hematopoietic tissues and cells, including immature T cells, but the role of <i>Fli-1</i> in T cell development has not been closely examined. To address this we retrovirally overexpressed <i>Fli-1</i> in various <i>in vitro</i> and <i>in vivo</i> settings and analysed its effect on T cell development. We found that <i>Fli-1</i> overexpression perturbed the DN to DP transition and inhibited CD4 development whilst enhancing CD8 development both <i>in vitro</i> and <i>in vivo</i>. Surprisingly, <i>Fli-1</i> overexpression <i>in vivo</i> eventuated in development of pre-T cell lymphoblastic leukaemia/lymphoma (pre-T LBL). Known <i>Fli-1</i> target genes such as the pro-survival <i>Bcl-2</i> family members were not found to be upregulated. In contrast, we found increased NOTCH1 expression in all <i>Fli-1</i> T cells and detected <i>Notch1</i> mutations in all tumours. These data show a novel function for <i>Fli-1</i> in T cell development and leukaemogenesis and provide a new mouse model of pre-T LBL to identify treatment options that target the <i>Fli-1</i> and <i>Notch1</i> signalling pathways.</p>