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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

Fli-1-induced pre-T LBL perturbs thymic, splenic and bone marrow architecture.Representative tissue sections (Haematoxylin & Eosin stain) of MigR1 and Fli-1 mice. MigR1 sections show normal organ architecture, whereas Fli-1 sections show thymus and spleen architecture effaced by small infiltrating malignant lymphocytes also present in the Fli-1 sternum. A. Thymus (x10 magnification). B. Spleen (x10 magnification). C. Sternum (x40 magnification).
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pone-0062346-g003: Fli-1-induced pre-T LBL perturbs thymic, splenic and bone marrow architecture.Representative tissue sections (Haematoxylin & Eosin stain) of MigR1 and Fli-1 mice. MigR1 sections show normal organ architecture, whereas Fli-1 sections show thymus and spleen architecture effaced by small infiltrating malignant lymphocytes also present in the Fli-1 sternum. A. Thymus (x10 magnification). B. Spleen (x10 magnification). C. Sternum (x40 magnification).

Mentions: Histology sections of MigR1 and Fli-1 thymus, spleen, liver and sternum (BM) revealed a significant infiltration of small cells in all tissues of Fli-1 transplanted mice (Figure 3). Specifically, the Fli-1 thymus had lost its normal cortical-medullary demarcation and was completely permeated with malignant T cells (Figure 3A). The Fli-1 spleen had no B cell follicles whilst the MigR1 control spleen did (Figure 3B. arrowheads). Finally, the bone marrow of the Fli-1 sternum was filled with uniform-sized cells in comparison to the more sparse heterogeneity of the bone marrow cells from the MigR1 control (Figure 3C). These data are consistent with the flow cytometry results demonstrating that Fli-1 transplanted mice had leukaemic cells throughout the thymus, spleen, lymph node, liver and bone marrow.


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)

Fli-1-induced pre-T LBL perturbs thymic, splenic and bone marrow architecture.Representative tissue sections (Haematoxylin & Eosin stain) of MigR1 and Fli-1 mice. MigR1 sections show normal organ architecture, whereas Fli-1 sections show thymus and spleen architecture effaced by small infiltrating malignant lymphocytes also present in the Fli-1 sternum. A. Thymus (x10 magnification). B. Spleen (x10 magnification). C. Sternum (x40 magnification).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0062346-g003: Fli-1-induced pre-T LBL perturbs thymic, splenic and bone marrow architecture.Representative tissue sections (Haematoxylin & Eosin stain) of MigR1 and Fli-1 mice. MigR1 sections show normal organ architecture, whereas Fli-1 sections show thymus and spleen architecture effaced by small infiltrating malignant lymphocytes also present in the Fli-1 sternum. A. Thymus (x10 magnification). B. Spleen (x10 magnification). C. Sternum (x40 magnification).
Mentions: Histology sections of MigR1 and Fli-1 thymus, spleen, liver and sternum (BM) revealed a significant infiltration of small cells in all tissues of Fli-1 transplanted mice (Figure 3). Specifically, the Fli-1 thymus had lost its normal cortical-medullary demarcation and was completely permeated with malignant T cells (Figure 3A). The Fli-1 spleen had no B cell follicles whilst the MigR1 control spleen did (Figure 3B. arrowheads). Finally, the bone marrow of the Fli-1 sternum was filled with uniform-sized cells in comparison to the more sparse heterogeneity of the bone marrow cells from the MigR1 control (Figure 3C). These data are consistent with the flow cytometry results demonstrating that Fli-1 transplanted mice had leukaemic cells throughout the thymus, spleen, lymph node, liver and bone marrow.

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