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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carcinogenesis / immunology*
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Gene Expression
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Hematopoietic Stem Cells / metabolism*
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Humans
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Intracellular Space / genetics
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Mice
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Mice, Inbred C57BL
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Organ Specificity
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / immunology*
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / pathology*
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Proto-Oncogene Protein c-fli-1 / genetics*
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Proto-Oncogene Proteins c-bcl-2 / genetics
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RNA, Messenger / genetics
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Receptor, Notch1 / genetics
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T-Lymphocytes / cytology*
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T-Lymphocytes / immunology*
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Up-Regulation / immunology
Substances
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Proto-Oncogene Protein c-fli-1
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Proto-Oncogene Proteins c-bcl-2
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RNA, Messenger
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Receptor, Notch1
Grants and funding
This work was supported by an NHMRC Project Grant #559004 and in part by the Victorian Government’s OIS Program. DI receives support from the Cancer Council of Victoria and the Leukaemia Foundation of Australia. AW receives support from the Leukaemia Foundation of Australia and the Victorian Cancer Agency. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.