Disease relevance of Fli1

• Hemorrhage, impaired hematopoiesis, and lethality in mouse embryos carrying a targeted disruption of the Fli1 transcription factor [1].
• 5. Histological examinations and in situ hybridization reveal disorganization of columnar epithelium and the presence of hematomas within the neuroepithelium and disruption of the basement membrane lying between this and mesenchymal tissues, both of which express Fli1 at the time of hemorrhaging [1].
• Restriction map analysis shows that this region is identical to the Fli-1 locus identified in Friend murine leukemia virus-induced erythroleukemia cell lines and thus may contain sequences also responsible for the development of mouse non-T-, non-B-cell lymphomas [2].
• Significantly, the leukemic blasts express erythroid markers and consistently contain proviral integrations in the Fli1 locus, a target of Friend MuLV (F-MuLV) during erythroleukemia induction [3].
• Erythroleukemia induction by Friend murine leukemia virus: insertional activation of a new member of the ets gene family, Fli-1, closely linked to c-ets-1 [4].

High impact information on Fli1

• The involvement of the murine Fli-1, Spi-1, and avian v-ets genes in erythroleukemia induction suggests that activation of ets gene family members plays an important role in the progression of these multistage malignancies [4].
• To determine the transcriptional domain defined by Fli-1, we have isolated a cDNA clone that is highly expressed only in erythroleukemia cell lines with Fli-1 rearrangements [4].
• PFGE analysis localized Fli-1 within 240 kb of the ets-1 proto-oncogene on mouse chromosome 9 and human chromosome 11q23, suggesting that ets-1 and Fli-1 arose from a common ancestral gene by gene duplication [4].
• Fli-1 is required for murine vascular and megakaryocytic development and is hemizygously deleted in patients with thrombocytopenia [5].
• Thus, Fli-1 appears to define a distinct locus specifically involved in the induction of erythroid leukemias by F-MuLV [6].

Biological context of Fli1

• Taken together, these results provide in vivo evidence for the role of Fli1 in the regulation of hematopoiesis and hemostasis [1].
• This gene, Prss14 (protease, serine, 14), was mapped to mouse chromosome 9 and is closely linked to the Fli1 (Friend leukemia integration 1) gene [7].
• Targeted disruption of the Friend leukemia integration 1 (Fli-1) proto-oncogene results in severe dysmegakaryopoiesis and embryonic lethality [8].
• The sorted Fli-1(-/-) bone marrow cells revealed specific down-regulation of CCAAT/enhancer binding protein-alpha (C/EBPalpha) and C/EBPepsilon, and the receptors for granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF), consistent with their critical roles in granulopoiesis [8].
• Site selection analysis indicated that the binding site preferred by mElf-1 is very similar to that of the Drosophila melanogaster homologue, E74, and to that of Fli-1, another Ets family member [9].

Anatomical context of Fli1

• Among these factors, Ets1, Erg1 and Fli1 are expressed in endothelial cells during angiogenesis in normal and pathological development [10].
• Clonal culture studies of bone marrow cells revealed increased numbers of granulocytic and early erythroid progenitors in the Fli-1(+/-) cells [8].
• Collectively, these observations suggest previously unknown physiologic roles for Fli-1 in granulocytic, erythroid, and NK cell proliferation and differentiation [8].
• Dysregulation of granulocyte, erythrocyte, and NK cell lineages in Fli-1 gene-targeted mice [8].
• Analyses of lineage expression of Fli-1(+/-) and Fli-1(-/-) cells in the peripheral blood and bone marrow of chimeric mice consistently demonstrated reduced numbers of neutrophilic granulocytes and monocytes and increased numbers of natural killer (NK) cells [8].

Associations of Fli1 with chemical compounds

• Finally, we show that transfection of constitutive or inducible Fli-1 expression vectors in SFFV-transformed cells inhibits their erythroid differentiation induced by HMBA [11].

Physical interactions of Fli1

• We also identified that Fli-1 DNA binding increased in G-CSF-treated cells compared with untreated cells [12].
• In previous studies we demonstrated that Tel binds to Fli-1 and blocks transactivation of megakaryocytic promoters by Fli-1 [13].

Regulatory relationships of Fli1

• G-CSF induces stabilization of ETS protein Fli-1 during myeloid cell development [12].
• This phenotype was corrected by crossing the Fli-1 deficient mice expressing Fli-1 cDNA [14].

Other interactions of Fli1

• Finally, we showed that the half-life of Fli-1 is prolonged in G-CSF-treated cells compared with control-treated cells [12].
• Subsequent molecular analysis demonstrated that both the -8 enhancer and the promoter depend on conserved Ets sites, which were bound in endothelial cells in vivo by Fli-1, Erg, and Elf-1 [15].
• Fli-1(+/-) MRL/lpr mice had significantly decreased serum levels of total IgG and anti-dsDNA Abs as disease progressed [16].
• Retroviral insertional activation of Fli-1 is the first detectable genetic alteration associated with F-MuLV-induced primary erythroleukemias, while mutations within p53 are only observed in Epo-dependent (ED) cell lines derived from syngeneic mice serially transplanted with F-MuLV-induced primary erythroleukemias [17].
• A human Fli-1-derived genomic fragment containing the GATA/EBS led to enhanced transcription when positioned upstream of the SV40 promoter in the erythroleukemic HEL cell line [18].

Analytical, diagnostic and therapeutic context of Fli1

• Transplantation studies using sorted Fli-1 mutant cells produced similar findings [8].
• Generation of a novel Fli-1 protein by gene targeting leads to a defect in thymus development and a delay in Friend virus-induced erythroleukemia [14].
• We report in this study that MRL/lpr mice, an animal model of systemic lupus erythematosus, have increased splenic expression of Fli-1 protein compared with BALB/c mice [16].
• As an approach to evaluate the contribution of Cas-Br-E MCF recombinant formation in cis-activation of proto-oncogenes, we analyzed the structure of the Fli-1- and Evi-1-associated proviruses by Southern blot hybridization [19].
• Studies of the intracellular penetration by confocal microscopy in NIH/3T3 EWS-Fli1 cells showed that nanocapsules improved the intracellular penetration of siRNA with mainly a cytoplasmic localization [20].

References