title: Fli-1 overexpression in hematopoietic progenitors deregulates T cell development and induces pre-T cell lymphoblastic leukaemia/lymphoma.
abstract: The Ets transcription factor Fli-1 is preferentially expressed in hematopoietic tissues and cells, including immature T cells, but the role of Fli-1 in T cell development has not been closely examined. To address this we retrovirally overexpressed Fli-1 in various in vitro and in vivo settings and analysed its effect on T cell development. We found that Fli-1 overexpression perturbed the DN to DP transition and inhibited CD4 development whilst enhancing CD8 development both in vitro and in vivo. Surprisingly, Fli-1 overexpression in vivo eventuated in development of pre-T cell lymphoblastic leukaemia/lymphoma (pre-T LBL). Known Fli-1 target genes such as the pro-survival Bcl-2 family members were not found to be upregulated. In contrast, we found increased NOTCH1 expression in all Fli-1 T cells and detected Notch1 mutations in all tumours. These data show a novel function for Fli-1 in T cell development and leukaemogenesis and provide a new mouse model of pre-T LBL to identify treatment options that target the Fli-1 and Notch1 signalling pathways.
authors.affiliation: Haematology and Leukaemia Unit, St. Vincent's Institute, University of Melbourne, Fitzroy, Victoria, Australia.
authors.forename: Monique F M A
authors.initials: MF
authors.lastname: Smeets
authors.forename: Angela C
authors.initials: AC
authors.lastname: Chan
authors.forename: Samantha
authors.initials: S
authors.lastname: Dagger
authors.forename: Cara K
authors.initials: CK
authors.lastname: Bradley
authors.forename: Andrew
authors.initials: A
authors.lastname: Wei
authors.forename: David J
authors.initials: DJ
authors.lastname: Izon
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000276:immunology*; D015870:Gene Expression; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D042541:Intracellular Space / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051881:Receptor, Notch1 / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology
chemical_list: D051789:Proto-Oncogene Protein c-fli-1; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051881:Receptor, Notch1