The ets transcription factor Fli-1 in development, cancer and disease

Abstract

Friend leukemia virus-induced erythroleukemia-1 (Fli-1), an E26 transformation specific (ETS) transcription factor, was isolated a quarter century ago through a retrovirus mutagenesis screen. Fli-1 has since been recognized to play critical roles in normal development and homeostasis. For example, it transcriptionally regulates genes that drive normal hematopoiesis and vasculogenesis. Indeed, Fli-1 is one of 10 key regulators of hematopoietic stem/progenitor cell maintenance and differentiation. Aberrant expression of Fli-1 also underlies a number of virally induced leukemias, including Friend virus-induced erythroleukemia and various types of human cancers, and it is the target of chromosomal translocations in childhood Ewing's sarcoma. Abnormal expression of Fli-1 is important in the etiology of autoimmune diseases such as systemic lupus erythematosus and systemic sclerosis. These studies establish Fli-1 as a strong candidate for drug development. Despite difficulties in targeting transcription factors, recent studies identified small-molecule inhibitors for Fli-1. Here we review past and ongoing research on Fli-1 with emphasis on its mechanistic function in autoimmune disease and malignant transformation. The significance of identifying Fli-1 inhibitors and their clinical applications for treatment of disease and cancer with deregulated Fli-1 expression are discussed.

Figure 1

(A) Fli-1 overexpression in erythroblasts induces erythroleukemias by inhibiting differentiation. (B) Fli-1 over-expression in erythroblasts results in a switch from Epo-induced differentiation to proliferation. Fli-1 regulates this process through its target genes, which affect apoptosis, differentiation and proliferation. HSC: Hematopoietic Stem Cells; BFU-E: Burst Forming Units-Erythroid; RBC: Red Blood Cells.

Figure 2

(A) The fli-1 promoter contains a GAn microsatellite that is polymorphic in lupus prone mice. Shown is a sequence comparison of fli-1 promoter regions containing the GAn microsatellite from three mouse strains. The GAn microsatellite sequence, located in the 5′ end of exon 1 and begins at bp -321, is marked. Transcription of the Fli-1 gene negatively correlates with size of the GAn repeats (adopted from Ref. ). (B) Effect of the GAn microsatellite repeats in the fli-1 promoter on susceptibility to Leishmenia. The location of GA polymorphism between C57BL/6 and BALB/c are marked (Adopted from Ref ).

Figure 3

A model for SSc induction by Fli-1. In fibroblasts, the phosphorylation of C-Abl by TGF-β induces nuclear translocation of PKCδ. In the nucleus, PKCδ phosphorylates Fli-1 at threonine 312, which initiates acetylation of Fli-1 by PCAF/P300/CBP, resulting in dissociation of Fli-1 from the Col1A2 promoter and transcriptional de-repression. Induction of collagen expression through Fli-1 phosphorylation/acetylation is proposed as a mechanism for SSC.

Figure 4

Aberrant Fli-1 expression enhances hallmarks of malignant transformation and immune response.