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

Abstract

Friend Leukemia Virus Induced erythroleukemia-1 (Fli-1), an 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 aetiology of auto-immune diseases such as Systemic Lupus Erythematosus (SLE) and Systemic Sclerosis (SSc). 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.

A screen for Fli-1 transcriptional modulators identifies PKC agonists that induce erythroid to megakaryocytic differentiation and suppress leukemogenesis

“…Transcription factors (TFs) are frequently modulated during cancer initiation and progression [1, 2]. Despite difficulties in targeting TFs for inhibition, new strategies including siRNA/miRNA knockdown, disruption of protein-protein interaction and modulation of chromatin accessibility are being developed to meet this challenge [1].…”

“…Despite difficulties in targeting TFs for inhibition, new strategies including siRNA/miRNA knockdown, disruption of protein-protein interaction and modulation of chromatin accessibility are being developed to meet this challenge [1]. Members of ETS family of TFs are often altered in various cancers, including leukemia [2]. The Friend Leukemia virus integration-1 (Fli-1), a member of ETS gene family, is activated by retroviral insertional mutagenesis in F-MuLV-induced erythroleukemias [3, 4].…”

Pro-inflammatory effect of a traditional Chinese medicine formula with potent anti-cancer activity in vitro impedes tumor inhibitory potential in vivo

“…2A and B). Fli-1 is a critical player in the induction and progression of F-MuLV-induced erythroleukemia (6,16–18). Notably, C54 markedly downregulated the expression of Fli-1 in HEL and CB7 cells, as determined by western blot analysis (Fig.…”

“…As Fli-1 expression serves an important role in the survival of erythroleukemic cells, and Fli-1 is known to be expressed in various leukemic cells, C54 represents a powerful drug for the treatment of hematological malignancies (16,30). Thus, administration of C54 with a powerful anti-inflammatory drug could be a promising approach for the treatment of Fli-1-overexpressing leukemias.…”

Friend leukemia virus integration 1 is a predictor of poor prognosis of breast cancer and promotes metastasis and cancer stem cell properties of breast cancer cells

“…FLI‐1 is preferentially expressed in the hematopoietic and vascular endothelial cells and plays an important role in normal cell function and malignant transformation 6, 7. It has been widely accepted as an oncogene contributing to various malignancies, such as malignant hematological diseases and some solid tumors, including breast cancer 8, 9, 10, 11, 12, 13, 14.…”