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Fli-1 overexpression in hematopoietic progenitors deregulates T cell development and induces pre-T cell lymphoblastic leukaemia/lymphoma.

Smeets MF, Chan AC, Dagger S, Bradley CK, Wei A, Izon DJ - PLoS ONE (2013)

Bottom Line: 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.In contrast, we found increased NOTCH1 expression in all Fli-1 T cells and detected Notch1 mutations in all tumours.

View Article: PubMed Central - PubMed

Affiliation: Haematology and Leukaemia Unit, St. Vincent's Institute, University of Melbourne, Fitzroy, Victoria, Australia.

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.

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Related in: MedlinePlus

No upregulation of pro-survival Bcl-2 family mRNA in Fli-1 pre-T LBL.RNA was isolated from MigR1 control (Mig), Fli-1 primary, secondary (2°) and in vitro Fli-1 pre-T LBL cells from the thymus, spleen or liver and cDNA was subjected to Q-PCR for the expression of Bcl-2, Bcl-xL and Mcl-1 mRNA. Samples were normalized to GAPDH levels and are shown on a log scale relative to the median MigR1 value, which was set to 1. T = thymus, S = spleen, L = liver.
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pone-0062346-g005: No upregulation of pro-survival Bcl-2 family mRNA in Fli-1 pre-T LBL.RNA was isolated from MigR1 control (Mig), Fli-1 primary, secondary (2°) and in vitro Fli-1 pre-T LBL cells from the thymus, spleen or liver and cDNA was subjected to Q-PCR for the expression of Bcl-2, Bcl-xL and Mcl-1 mRNA. Samples were normalized to GAPDH levels and are shown on a log scale relative to the median MigR1 value, which was set to 1. T = thymus, S = spleen, L = liver.

Mentions: Fli-1 has been demonstrated to upregulate Bcl-2 in erythroleukaemia [26]. Therefore, we analysed primary and secondary Fli-1 leukaemias and MigR1 controls for Bcl-2, Bcl-xL and Mcl-1 mRNA expression by Q-PCR (Figure 5). Surprisingly, all Fli-1 pre-T LBLs, whether primary, secondary or grown in vitro had lower levels of Bcl-2 family members, Bcl-2, Bcl-xL and Mcl-1 (Figure 5). These data show that overexpression of the pro-survival Bcl-2 family members are unlikely to be involved in the induction of Fli-1 pre-T LBL.


Fli-1 overexpression in hematopoietic progenitors deregulates T cell development and induces pre-T cell lymphoblastic leukaemia/lymphoma.

Smeets MF, Chan AC, Dagger S, Bradley CK, Wei A, Izon DJ - PLoS ONE (2013)

No upregulation of pro-survival Bcl-2 family mRNA in Fli-1 pre-T LBL.RNA was isolated from MigR1 control (Mig), Fli-1 primary, secondary (2°) and in vitro Fli-1 pre-T LBL cells from the thymus, spleen or liver and cDNA was subjected to Q-PCR for the expression of Bcl-2, Bcl-xL and Mcl-1 mRNA. Samples were normalized to GAPDH levels and are shown on a log scale relative to the median MigR1 value, which was set to 1. T = thymus, S = spleen, L = liver.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3646842&req=5

pone-0062346-g005: No upregulation of pro-survival Bcl-2 family mRNA in Fli-1 pre-T LBL.RNA was isolated from MigR1 control (Mig), Fli-1 primary, secondary (2°) and in vitro Fli-1 pre-T LBL cells from the thymus, spleen or liver and cDNA was subjected to Q-PCR for the expression of Bcl-2, Bcl-xL and Mcl-1 mRNA. Samples were normalized to GAPDH levels and are shown on a log scale relative to the median MigR1 value, which was set to 1. T = thymus, S = spleen, L = liver.
Mentions: Fli-1 has been demonstrated to upregulate Bcl-2 in erythroleukaemia [26]. Therefore, we analysed primary and secondary Fli-1 leukaemias and MigR1 controls for Bcl-2, Bcl-xL and Mcl-1 mRNA expression by Q-PCR (Figure 5). Surprisingly, all Fli-1 pre-T LBLs, whether primary, secondary or grown in vitro had lower levels of Bcl-2 family members, Bcl-2, Bcl-xL and Mcl-1 (Figure 5). These data show that overexpression of the pro-survival Bcl-2 family members are unlikely to be involved in the induction of Fli-1 pre-T LBL.

Bottom Line: 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.In contrast, we found increased NOTCH1 expression in all Fli-1 T cells and detected Notch1 mutations in all tumours.

View Article: PubMed Central - PubMed

Affiliation: Haematology and Leukaemia Unit, St. Vincent's Institute, University of Melbourne, Fitzroy, Victoria, Australia.

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.

Show MeSH
Related in: MedlinePlus