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.

The ETS transcription factor Fli-1 controls the expression of genes involved in hematopoiesis including cell proliferation, survival, and differentiation. Dysregulation of Fli-1 induces hematopoietic and solid tumors, rendering it an important target for therapeutic intervention. Through high content screens of a library of chemicals isolated from medicinal plants in China for inhibitors of a Fli-1 transcriptional reporter cells, we hereby report the identification of diterpenoid-like compounds that strongly inhibit Fli-1 transcriptional activity. These agents suppressed the growth of erythroleukemic cells by inducing apoptosis and differentiation. They also inhibited survival and proliferation of B-cell leukemic cell lines as well as primary B-cell lymphocytic leukemia (B-CLL) isolated from 7 patients. Moreover, these inhibitors blocked leukemogenesis in a mouse model of erythroleukemia, in which Fli-1 is the driver of tumor initiation. Computational docking analysis revealed that the diterpenoid-like compounds bind with high affinity to nucleotide residues in a pocket near the major groove within the DNA-binding sites of Fli-1. Functional inhibition of Fli-1 by these compounds triggered its further downregulation through miR-145, whose promoter is normally repressed by Fli-1. These results uncover the importance of Fli-1 in leukemogenesis, a Fli-1-miR145 autoregulatory loop and new anti-Fli-1 diterpenoid agents for the treatment of diverse hematological malignancies overexpressing this transcription factor.

Triple-negative breast cancer (TNBC) represents a heterogeneous group of ER- and HER2-negative tumors with poor clinical outcome. We recently reported that Pten-loss cooperates with low expression of microRNA-145 to induce aggressive TNBC-like lesions in mice. To systematically identify microRNAs that cooperate with PTEN-loss to induce aggressive human BC, we screened for miRNAs whose expression correlated with PTEN mRNA levels and determined the prognostic power of each PTEN-miRNA pair alone and in combination with other miRs. Publically available data sets with mRNA, microRNA, genomics, and clinical outcome were interrogated to identify miRs that correlate with PTEN expression and predict poor clinical outcome. Alterations in genomic landscape and signaling pathways were identified in most aggressive TNBC subgroups. Connectivity mapping was used to predict response to therapy. In TNBC, PTEN loss cooperated with reduced expression of hsa-miR-4324, hsa-miR-125b, hsa-miR-381, hsa-miR-145, and has-miR136, all previously implicated in metastasis, to predict poor prognosis. A subgroup of TNBC patients with PTEN-low and reduced expression of four or five of these miRs exhibited the worst clinical outcome relative to other TNBCs (hazard ratio (HR) = 3.91; P < 0.0001), and this was validated on an independent cohort (HR = 4.42; P = 0.0003). The PTEN-low/miR-low subgroup showed distinct oncogenic alterations as well as TP53 mutation, high RB1-loss signature and high MYC, PI3K, and β-catenin signaling. This lethal subgroup almost completely overlapped with TNBC patients selected on the basis of Pten-low and RB1 signature loss or β-catenin signaling-high. Connectivity mapping predicted response to inhibitors of the PI3K pathway. This analysis identified microRNAs that define a subclass of highly lethal TNBCs that should be prioritized for aggressive therapy.