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.

MicroRNAs (miRNAs), a class of short, single-stranded non-coding RNAs, regulate and control gene expression in eukaryotes by degrading mRNA at the post-transcriptional level. Regulation by miRNAs involves a plethora of biological processes, such as cell differentiation, proliferation, metastasis, metabolism, apoptosis, tumorigenesis and others. miRNAs also represent a powerful tool in disease diagnosis and prognosis. The miR-17-92 cluster, one of the most extensively investigated microRNA clusters, comprises six mature miRNA members, including miR-17, miR-18a, miR-19a, miR-19b, miR-20a and miR-92a. Originally identified as being involved in tumorigenesis, it is currently evident that the expression of the miR-17-92 cluster is upregulated in a wide range of tumor cells and cancer types; thus, this cluster has been identified as a potential oncogene. Considering the growing interest in the field of miR-17-92 research, we herein review recent advances in the expression and regulation of this cluster in various cancer cells, discuss the proposed mechanism of action for tumorigenesis and tumor development, and propose clinical and therapeutic applications for miR-17-92 cluster members, such as potential cancer biomarkers.

The ETS-related transcription factor Fli-1 affects many developmental programs including erythroid and megakaryocytic differentiation, and is frequently de-regulated in cancer. Fli-1 was initially isolated following retrovirus insertional mutagenesis screens for leukemic initiator genes, and accordingly, inhibition of this transcription factor can suppress leukemia through induction of erythroid differentiation. To search for modulators of Fli-1, we hereby performed repurposing drug screens with compounds isolated from Chinese medicinal plants. We identified agents that can transcriptionally activate or inhibit a Fli-1 reporter. Remarkably, agents that increased Fli-1 transcriptional activity conferred a strong anti-cancer activity upon Fli-1-expressing leukemic cells in culture. As opposed to drugs that suppress Fli1 activity and lead to erythroid differentiation, growth suppression by these new Fli-1 transactivating compounds involved erythroid to megakaryocytic conversion (EMC). The identified compounds are structurally related to diterpene family of small molecules, which are known agonists of protein kinase C (PKC). In accordance, these PKC agonists (PKCAs) induced PKC phosphorylation leading to activation of the mitogen-activated protein kinase (MAPK) pathway, increased cell attachment and EMC, whereas pharmacological inhibition of PKC or MAPK diminished the effect of our PKCAs. Moreover, in a mouse model of leukemia initiated by Fli-1 activation, the PKCA compounds exhibited strong anti-cancer activity, which was accompanied by increased presence of CD41/CD61 positive megakaryocytic cells in leukemic spleens. Thus, PKC agonists offer a novel approach to combat Fli-1-induced leukemia, and possibly other cancers,by inducing EMC in part through over-activation of the PKC-MAPK-Fli-1 pathway.

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