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1
Peterlin, Pierre, Joelle Gaschet, Thierry Guillaume, Alice Garnier, Marion Eveillard, Amandine Le Bourgeois, Michel Cherel, et al. "A New Cytokine-Based Stratification Is Highly Predictive of Survivals in AML Patients." Blood 134, Supplement_1 (November 13, 2019): 1412. http://dx.doi.org/10.1182/blood-2019-125774.
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Introduction: Recently, a significant impact of the kinetics of Fms-like tyrosine kinase 3 ligand concentration (FLc) during induction (day[D]1 to D22) has been reported on survivals in first-line acute myeloid leukemia (AML) patients (pts) (Peterlin et al, 2019). Three different FLc profiles were disclosed i) sustained increase of FLc (FLI group, good-risk), ii) increase from D1 to D15, then decrease at D22 (FLD group, intermediate-risk) and iii) stagnation of low levels (<1000 pg/mL, FLL group, high-risk). An update of this prospective monocentric study (www.ClinicalTrials.gov NCT02693899) is presented here evaluating also retrospectively the impact on outcomes of 6 other cytokine level profiles during induction. Methods: Between 05/2016 and 01/2018, 62 AML pts at diagnosis (median age 59 yo [29-71], <60 yo n=33) eligible for first intensive induction were included and provided informed consent. They received standard of care first-line chemotherapy. Serum samples collected on D1, 8, 15 & 22 of induction were frozen-stored until performing ELISA for FL, TNFa, SCF, IL-1b, IL-6, IL-10, GM-CSF. Normal values were assessed in 5 healthy controls. Pts outcomes considered were relapse/leukemia-free (LFS) and overall (OS) survivals. Results: FLI, FLD and FLL profiles were observed for 26, 22 and 14 pts respectively. A total of 372 samples were assayed for the 6 other cytokines. Median concentrations at D1, D8, D15, D22 for these 6 cytokines were as follows, considering the whole cohort (and healthy donors): TNFa: 0.53, 0, 0, 0 (0); SCF: 5.91, 0, 0, 0 (3); IL-1b : 0, 0, 0, 0 (0); IL-6: 4.85, 16.28, 10.11, 7.1 (0), IL-10: 0, 0, 0, 0 (0) and GM-CSF:1.63, 1.8, 0.67, 1.34 (9.98). Median IL-6 and GM-CSF levels, compared to healthy controls, were respectively higher and lower during induction. No significant difference was observed in terms of median cytokine concentrations at any time when comparing the three FL sub-groups or FLI vs FLD pts. With a median follow-up of 28 months (range: 17-37), FLI and FLD pts show now similar 2-y LFS (62.9% vs 59%, p=0.63) and OS (69.2% vs 63.6%, p=0.70). FLL pts have a significantly higher rate of relapse (85,7% vs FLI 19,2% vs FLD 32%, p=0,0001). Comparing FLL vs FLI+FLD pts disclosed significantly different LFS (7.1% vs 61.1%, p<0.001) but not OS (36.7% vs 66.6%, p=0.11). In univariate analysis, 2y LFS and OS were not affected by the concentration (< or > median) of the 7 cytokines studied except for LFS and GM-CSFc at D8 (p=0,04) and D15 (p=0,08), for LFS and FLc at D1 (p=0.06), D8 (p=0,03), D15 (p=0,04) and D22 (p=0,03) and for OS and GM-CSF at D15 (p=0.08). A significant association between LFS was observed with ELN 2017 risk stratification (2-y LFS: favorable: 68,1% vs intermediate: 48,1% vs unfavorable: 30,7%, p=0.03) but not OS (2 y: 77% vs 55,5% vs 46,1%, p=0.09). Multivariate analysis showed that no factor was independently associated with OS while LFS remained significantly associated with the FLc profile (FLL vs others, HR: 5.79. 95%CI: 2.48-13.53, p<0.0001) and GM-CSF at D15 (HR: 0.45; 95%CI: 0.20-0.98, p=0.04) but not with ELN 2017 risk stratification (p=0.06). Cytokine levels were then assessed to try to better discriminate FLI and FLD pts. A significant higher IL-6 level at D22 was found in relapsed or deceased FLI/FLD pts (median:15,34 vs 5,42 pg/mL, p=0,04). FLI/FLD pts with low IL-6 at D22 (< median, 15.5 pg/mL, n=35 vs n=14 with high level) had significant better 2y LFS and OS (74,2% vs 38,4%, p=0,005 and 77,1% vs 38,4%, p=0,009, respectively). A new prognostic risk-stratification could thus be proposed, i.e. FLI/FLD with IL-6 <15.5 pg/mL (favorable), FLI/FLD with IL-6 >15.5 pg/mL (intermediate) and FLL (unfavorable). This new classification was considered for a second multivariate analysis, showing that it is the strongest factor associated with OS (p=0.006, ELN p=0.03, FL profile p=0.04) and LFS (p<0.0001, ELN p=0.005, GM-CSFc D15 p=0.03) (figure 1). Conclusion: This study confirms stagnation of low FLc during AML induction as a strong poor prognosis factor. Moreover, IL-6 levels at D22 further discriminate FLI/FLD pts. Thus, a new cytokine-based risk-stratification integrating FL kinetics and IL-6 levels during induction may help to better predict outcomes in first-line AML patients. These results need to be validated on a larger cohort of AML patients while anti-IL-6 therapy should be tested in combination with standard 3+7 chemotherapy. Figure 1 Disclosures Peterlin: AbbVie Inc: Consultancy; Jazz Pharma: Consultancy; Daiichi-Sankyo: Consultancy; Astellas: Consultancy. Moreau:Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Chevallier:Jazz Pharmaceuticals: Honoraria; Incyte: Consultancy, Honoraria; Daiichi Sankyo: Honoraria.
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Olubamwo, Olubunmi O., Jyrki K. Virtanen, Jussi Pihlajamaki, Pekka Mantyselka, and Tomi-Pekka Tuomainen. "Fatty liver index as a predictor of increased risk of cardiometabolic disease: finding from the Kuopio Ischaemic Heart Disease Risk Factor Study Cohort." BMJ Open 9, no. 9 (September 2019): e031420. http://dx.doi.org/10.1136/bmjopen-2019-031420.
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ObjectiveFatty liver disease (FLD), a global epidemic, is also a predictor of cardiometabolic disease (CMD) (type 2 diabetes or cardiovascular disease). Our objective was to examine whether progressive FLD, as assessed by fatty liver index (FLI), predicts increasing future CMD risk compared with relatively stable FLD, among middle-aged men.DesignProspective epidemiological study.SettingUniversity affiliated research centre in Kuopio, Eastern Finland.ParticipantsOur subjects were 501 men without CMD during the initial 4-year follow-up in the Kuopio Ischaemic Heart Disease Risk Factor Study cohort.Outcome measureOver the initial 4-year follow-up, 135 men (26.9%) had a significant (≥10) FLI increase. The association of 4-year FLI increase with incident CMD was analysed in multivariable-adjusted Cox regression models, adjusting for baseline constitutional and lifestyle factors (model 1) and, in addition, metabolic and inflammation biomarker factors (model 2).ResultsDuring a mean follow-up of 15 years, 301 new CMD cases occurred. We used subjects with low baseline FLI and no significant 4-year FLI increase as the reference. For subjects with intermediate baseline FLI and significant 4-year FLI increase, the HRs and 95% CIs for incident CMD in model 1 (2.13 (1.45 to 3.13)) and model 2 (1.73 (1.13 to 2.66)) exceeded values for subjects with similar baseline FLI without a significant 4-year change (HRs (95% CIs) were 1.36 (0.94 to 1.97) for model 1 and 1.18 (0.81 to 1.70) for model 2). They approached HRs (95% CI) for subjects who maintained high FLI over the 4 years (HRs (95% CIs) were 2.18 (1.54 to 3.10) in model 1 and 1.85 (1.21 to 2.82) in model 2).ConclusionPersons with significant FLI increase are likely with increasing CMD risk. Such persons should be evaluated for progressive FLD and CMD and managed to reduce CMD risk.
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May, W. A., S. L. Lessnick, B. S. Braun, M. Klemsz, B. C. Lewis, L. B. Lunsford, R. Hromas, and C. T. Denny. "The Ewing's sarcoma EWS/FLI-1 fusion gene encodes a more potent transcriptional activator and is a more powerful transforming gene than FLI-1." Molecular and Cellular Biology 13, no. 12 (December 1993): 7393–98. http://dx.doi.org/10.1128/mcb.13.12.7393.
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EWS/FLI-1 is a chimeric protein formed by a tumor-specific 11;22 translocation found in both Ewing's sarcoma and primitive neuroectodermal tumor of childhood. EWS/FLI-1 has been shown to be a potent transforming gene, suggesting that it plays an important role in the genesis of these human tumors. We now demonstrate that EWS/FLI-1 has the characteristics of an aberrant transcription factor. Subcellular fractionation experiments localized the EWS/FLI-1 protein to the nucleus of primitive neuroectodermal tumor cells. EWS/FLI-1 specifically bound in vitro an ets-2 consensus sequence similarly to normal FLI-1. When coupled to a GAL4 DNA-binding domain, the amino-terminal EWS/FLI-1 region was a much more potent transcriptional activator than the corresponding amino-terminal domain of FLI-1. Finally, EWS/FLI-1 efficiently transformed NIH 3T3 cells, but FLI-1 did not. These data suggest that EWS/FLI-1, functioning as a transcription factor, leads to a phenotype dramatically different from that of cells expressing FLI-1. EWS/FLI-1 could disrupt normal growth and differentiation either by more efficiently activating FLI-1 target genes or by inappropriately modulating genes normally not responsive to FLI-1.
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May, W. A., S. L. Lessnick, B. S. Braun, M. Klemsz, B. C. Lewis, L. B. Lunsford, R. Hromas, and C. T. Denny. "The Ewing's sarcoma EWS/FLI-1 fusion gene encodes a more potent transcriptional activator and is a more powerful transforming gene than FLI-1." Molecular and Cellular Biology 13, no. 12 (December 1993): 7393–98. http://dx.doi.org/10.1128/mcb.13.12.7393-7398.1993.
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EWS/FLI-1 is a chimeric protein formed by a tumor-specific 11;22 translocation found in both Ewing's sarcoma and primitive neuroectodermal tumor of childhood. EWS/FLI-1 has been shown to be a potent transforming gene, suggesting that it plays an important role in the genesis of these human tumors. We now demonstrate that EWS/FLI-1 has the characteristics of an aberrant transcription factor. Subcellular fractionation experiments localized the EWS/FLI-1 protein to the nucleus of primitive neuroectodermal tumor cells. EWS/FLI-1 specifically bound in vitro an ets-2 consensus sequence similarly to normal FLI-1. When coupled to a GAL4 DNA-binding domain, the amino-terminal EWS/FLI-1 region was a much more potent transcriptional activator than the corresponding amino-terminal domain of FLI-1. Finally, EWS/FLI-1 efficiently transformed NIH 3T3 cells, but FLI-1 did not. These data suggest that EWS/FLI-1, functioning as a transcription factor, leads to a phenotype dramatically different from that of cells expressing FLI-1. EWS/FLI-1 could disrupt normal growth and differentiation either by more efficiently activating FLI-1 target genes or by inappropriately modulating genes normally not responsive to FLI-1.
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Itkin, Tomer, Chaitanya R. Badwe, Sean Houghton, Yang Lin, Ying Liu, Peipei Guo, Jesus M. Gomez-Salinero, et al. "Fli-1 Transcriptionally Integrates Microenvironmental Cues Sensing By Self-Renewing Hematopoietic Stem and Progenitor Cells." Blood 134, Supplement_1 (November 13, 2019): 725. http://dx.doi.org/10.1182/blood-2019-126190.
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During adulthood and embryogenesis, fate decisions of hematopoietic stem and progenitor cells (HSPCs), such as specification, self-renewal, and differentiation are tightly regulated by their neighboring niche cells. Moreover, distinct types of niches supply differential cues to direct alternative cell fates for HSPCs. Yet, currently the intrinsic mechanisms balancing HSPC response obliqueness to microenvironmental signals are unknown. Friend Leukemia integration-1 (Fli-1), is an ETS transcription factor expressed by vascular beds and hematopoietic lineages. Fli-1 belongs to the "heptad factors" which are hypothesized to specify and sustain a hematopoietic cell fate. While Fli-1 overexpression is linked to leukemia, the functional role Fli-1 plays in HSPC specification and maintenance remains undefined. We show that inducible deletion of Fli-1 using a Rosa-CreERT2 transgenic adult mice (Fli-1ROSAΔ), results in a rapid thrombocytopenia-associated mortality. Transplantation of Fli-1ROSAΔ bone marrow (BM) cells into WT recipients, to exclude vascular-mediated defects, followed by induction of Fli-1 deletion, resulted with the same phenotype. In a set of modulated competitive transplantation experiments (differential induction time points pre- or post-transplant), we observed defective ability of Fli-1ROSAΔ HSPCs to lodge, engraft, and to sustain hematopoiesis post repopulation. Fli-1 deficient HSPCs exhibited reduced quiescent cell cycling status, a hallmark of stemness, and displayed enhanced apoptosis. Thus, Fli-1 is essential for previously unrecognized cell-autonomous HSPC functions. To determine whether Fli-1 modulates HSPC specification, Fli-1 was conditionally deleted using a developmental VE-cadherin (CDH5)-Cre transgenic model (Fli-1CDH5Δ). This resulted with premature mortality of Fli-1CDH5Δ embryos, accompanied with a hemorrhagic phenotype. Reduced numbers of hematopoietic cells were still detected in the AGM of e10.5 Fli-1CDH5Δ embryos. Conditional Fli-1 deletion using a developmental hematopoietic Vav-1 Cre transgenic model (Fli-1Vav-1Δ) resulted again with premature mortality. Reduced presence of embryonic Fli-1Vav-1Δ liver HSPCs was observed at e12.5. We also applied two in vitro co-culture systems, to study Fli-1 in endothelial to hematopoietic transition (EHT). First, isolated hemogenic endothelial cells (HEC) from WT and Fli-1ROSAΔ embryos were co-cultured with AGM-derived vascular niche. HECs isolated from Fli-1ROSAΔ AGM were still able to convert to CD45+ cells, however these cells did not expand on a vascular niche. Secondly, we have applied an endothelial to hematopoietic reprogramming system in which isolated lung ECs are virally introduced with DOX inducible FosB, Gfi1, Runx1, and Spi1 (FGRS) factors and co-cultured with vascular niche cells. Both WT and Fli-1ROSAΔ ECs were able to acquire a hemogenic like state resulting with a final capacity to convert into hematopoietic cells. Again, Fli-1ROSAΔ cells displayed lesser numbers of CD45+ cells at the end point, presumably due to impaired interaction with the vascular niche. Indeed, reduced expansion capacity was observed both for mature CD45+ and for HSPC derived from Fli-1CDH5Δ AGM region. Adult Fli-1ROSAΔ HSPCs exhibited the same niche-dependent expansion defect. Induction of Fli-1 deletion in vitro in adult HSPCs revealed loss of dependency on vascular niche inductive signals, as no additive expansion effect was observed for Fli-1ROSAΔ HSPCs in the presence of a vascular niche. Hence, Fli-1 is essential for HSPC expansion rather than hematopoietic specification. Differential RNA-seq analysis combined with epigenetic studies of expanding WT and Fli-1ROSAΔ HSPCs, revealed dysregulation of Fli-1-controlled pathways involved in transduction of microenvironmental signals for self-renewal. Unexpectedly, H3K27Ac analysis, a marker for transcriptional priming, revealed increased global acetylation of Fli-1ROSAΔ HSPCs' chromatin. Therefor, Fli-1 may not only perform as transcription activator, but foremostly as a genomic suppressor via modulation of histone acetylation status. Decrypting the mechanism(s) by which Fli-1 orchestrates HSPC self-renewal, may promote an improved expansion protocol of human HSPC pre-transplantation, and provide additional insights for microenvironmental sensing by Fli-1-dependent leukemic cells. Disclosures No relevant conflicts of interest to declare.
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Schutt, Steven Douglas, David Bastian, Hee-Jin Choi, Yongxia Wu, Mohammed Hanief Sofi, Hung Nguyen, Xian Zhang, and Xue-Zhong Yu. "Fli-1 Regulates Multiple T-Cell Subsets during Inflammatory Responses and Experimental Graft-Versus-Host Disease." Blood 134, Supplement_1 (November 13, 2019): 3201. http://dx.doi.org/10.1182/blood-2019-127577.
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Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a procedure undertaken to cure hematological malignancies, especially leukemia. Graft-Versus-Host Disease (GVHD) is a serious condition that often appears following allo-HCT. Friend Leukemia Virus Integration 1 (Fli-1) is a transcription factor highly expressed in cancers including erythroleukemia and acute myeloid leukemia while also implicated in pathogenesis of systemic lupus. We have interrogated the role of Fli-1 in T-cell responses by generating a novel T-cell specific conditional disruption of fli-1 where essential exons 3 and 4 of the gene are floxed and excised in the presence of CD4-Cre recombinase. Models of acute GVHD (aGVHD) and chronic GVHD (cGVHD) were tested utilizing hematopoietic cells from mice with a heterozygous (fli-1-/+ or Het) or homozygous (fli-1-/-or Null) disruption of the fli-1 gene, or from wild-type (fli-1+/+ or WT) littermate controls. At baseline, T cells among each of these three mouse strains showed no significant difference in CD44/CD62L expression or CD4+FoxP3+ (nTreg) frequencies. In the cGVHD model, BALB/c (H2Kd) recipients were infused with allogeneic B6 (H2Kb) genotype-respective bone marrow and splenocytes in order to induce cGVHD. Recipients that received fli-1-/+CD4Cre+ marrow and splenocytes demonstrated improved survival and mild cGVHD, whereas those that received fli-1-/-CD4Cre+ or WT donor cells developed serve cGVHD (Fig. 1 a-f). Cellular studies from lymphoid organs of cGVHD allo-HCT recipients revealed that disruption of fli-1 was associated with decreased frequencies of donor CD4+ cells expressing IL-17A, IFN-γ, T follicular-like (TFH-like) cell markers, and CD8+ cells expressing PD-1. In aGVHD settings, donor fli-1-/+CD4Cre+ T cells had a decreased ability to induce aGVHD compared to WT donor T cells and fli-1-/- donor T cells (Fig. 2 a-b). When investigating cellular mechanisms in aGVHD settings, we found that fli-1-/+CD4Cre+ T cells produced significantly lower IFN-γ early after T-cell activation in vivo compared to WT and fli-1-/-CD4Cre+ T cells (Fig. 2 c). To then investigate the role of Fli-1 in T cells beyond GVHD, we utilized a colitis model by transferring naïve CD4+ T cells (CD44-CD25-) into Rag2-/- syngeneic recipients. While fli-1+/+ T cells induced severe colitis as expected, fli-1-/- and fli--/+ T cells caused moderate and mild colitis, respectively. These results were consistent with those observed in GVHD models. To elucidate underlying mechanisms, we tested the effects of Fli-1 on antigen-specific T-cells using a MHC-II restricted TCR transgenic (Tg) mouse strain specific for HY-peptide. CD4+CD25- T cells from fli-1+/+, fli-1-/+, or fli-1-/- CD4Cre+ TCR-Tg mice were polarized in vitro with endogenous antigen presenting cells from spleen in presence of HY-peptide under iTreg- or Th17-polarizing conditions. Both fli-1-/+ and fli-1-/- TCR-tg T cells exhibited significant increases in iTreg (CD4+FoxP3+) frequencies and surface expression of iTreg functional markers (CD25, CD39, CD73, NRP-1), while also having significantly decreased frequencies of IL-17A producing T cells compared to WT-TCR-tg T cells. To further explore the molecular mechanisms, we retrieved fli-1+/+, fli-1-/+, or fli-1-/- donor T cells from recipient spleens after allo-HCT and did RNAseq analysis on these cells. RNAseq data reveals significant differences in mRNA expression within acute inflammatory response and positive regulation of the immune response enrichment pathways between fli-1-/+ T cells and littermate fli-1+/+ T cells, and to a lesser extent in fli-1-/- T cells (Fig. 2 d-f). Thus, reducing Fli-1 transcriptional activity represents a potential therapeutic concept toward ameliorating GVHD after allo-HCT, while simultaneously targeting cancers such as leukemia which typically overexpress Fli-1. Disclosures No relevant conflicts of interest to declare.
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Eisbacher, Michael, Melissa L. Holmes, Anthea Newton, Philip J. Hogg, Levon M. Khachigian, Merlin Crossley, and Beng H. Chong. "Protein-Protein Interaction between Fli-1 and GATA-1 Mediates Synergistic Expression of Megakaryocyte-Specific Genes through Cooperative DNA Binding." Molecular and Cellular Biology 23, no. 10 (May 15, 2003): 3427–41. http://dx.doi.org/10.1128/mcb.23.10.3427-3441.2003.
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ABSTRACT Friend leukemia integration 1 (Fli-1) is a member of the Ets family of transcriptional activators that has been shown to be an important regulator during megakaryocytic differentiation. We undertook a two-hybrid screen of a K562 cDNA library to identify transcription factors that interacted with Fli-1 and were potential regulators of megakaryocyte development. Here we report the physical interaction of Fli-1 with GATA-1, a well-characterized, zinc finger transcription factor critical for both erythroid and megakaryocytic differentiation. We map the minimal domains required for the interaction and show that the zinc fingers of GATA-1 interact with the Ets domain of Fli-1. GATA-1 has previously been shown to interact with the Ets domain of the Fli-1-related protein PU.1, and the two proteins appear to inhibit each other's activity. In contrast, we demonstrate that GATA-1 and Fli-1 synergistically activate the megakaryocyte-specific promoters GPIX and GPIbα in transient transfections. Quantitative electrophoretic mobility shift assays using oligonucleotides derived from the GPIX promoter containing Ets and GATA binding motifs reveal that Fli-1 and GATA-1 exhibit cooperative DNA binding in which the binding of GATA-1 to DNA is increased approximately 26-fold in the presence of Fli-1 (from 4.2 to 0.16 nM), providing a mechanism for the observed transcriptional synergy. To test the effect on endogenous genes, we stably overexpressed Fli-1 in K562 cells, a line rich in GATA-1. Overexpression of Fli-1 induced the expression of the endogenous GPIX and GPIbα genes as measured by Northern blot and fluorescence-activated cell sorter analysis. This work suggests that Fli-1 and GATA-1 work together to activate the expression of genes associated with the terminal differentiation of megakaryocytes.
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Juban, Gaëtan, Guillaume Giraud, Boris Guyot, Stéphane Belin, Jean-Jacques Diaz, Joëlle Starck, Christel Guillouf, Françoise Moreau-Gachelin, and François Morlé. "Spi-1 and Fli-1 Directly Activate Common Target Genes Involved in Ribosome Biogenesis in Friend Erythroleukemic Cells." Molecular and Cellular Biology 29, no. 10 (March 16, 2009): 2852–64. http://dx.doi.org/10.1128/mcb.01435-08.
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ABSTRACT Spi-1 and Fli-1 are ETS transcription factors recurrently deregulated in mouse erythroleukemia induced by Friend viruses. Since they share the same core DNA binding site, we investigated whether they may contribute to erythroleukemia by common mechanisms. Using inducible knockdown, we demonstrated that Fli-1 contributes to proliferation, survival, and differentiation arrest of erythroleukemic cells harboring an activated fli-1 locus. Similarly, we used inducible Fli-1 knockdown and either hexamethylenebisacetamide (HMBA)- or small interfering RNA-mediated Spi-1 knockdown to investigate their respective contributions in erythroleukemic cells harboring an activated spi-1 locus. In these cells, simple or double knockdown of both Spi-1 and Fli-1 additively contributed to induce proliferation arrest and differentiation. Transcriptome profiling revealed that virtually all transcripts affected by both Fli-1 knockdown and HMBA are affected in an additive manner. Among these additively downregulated transcripts, more than 20% encode proteins involved in ribosome biogenesis, and conserved ETS binding sites are present in their gene promoters. Through chromatin immunoprecipitation, we demonstrated the association of Spi-1 and Fli-1 on these promoters in Friend erythroleukemic cells. These data lead us to propose that the oncogenicity of Spi-1, Fli-1, and possibly other ETS transcription factors may involve their ability to stimulate ribosome biogenesis.
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Starck, Joëlle, Alexandre Doubeikovski, Sandrine Sarrazin, Colette Gonnet, Govinda Rao, Arthur Skoultchi, Jacqueline Godet, Isabelle Dusanter-Fourt, and François Morle. "Spi-1/PU.1 Is a Positive Regulator of the Fli-1 Gene Involved in Inhibition of Erythroid Differentiation in Friend Erythroleukemic Cell Lines." Molecular and Cellular Biology 19, no. 1 (January 1, 1999): 121–35. http://dx.doi.org/10.1128/mcb.19.1.121.
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ABSTRACT Spi-1/PU.1 and Fli-1 are two members of the ETS family of transcription factors whose expression is deregulated by proviral insertion in most erythroleukemic cell lines induced by the spleen focus-forming virus (SFFV) and Friend murine leukemia virus (F-MuLV) components of the Friend viral complex, respectively. In this study, we present evidence that transcription of the Fli-1 gene is positively regulated by Spi-1/PU.1 in SFFV-transformed cell lines: (i) all SFFV-transformed cell lines expressing Spi-1/PU.1 are characterized by a specific pattern of Fli-1 gene transcripts initiated in the −200 region instead of position −400 as reported for F-MuLV-transformed cell lines; (ii) these Fli-1 transcripts initiated in the −200 region are downregulated in parallel with that of Spi-1/PU.1 during hexamethylenebisacetamide (HMBA) induced differentiation; and (iii) Fli-1 transcription is upregulated in SFFV cells lines following stable transfection of a Spi-1/PU.1 expression vector. Furthermore, we found by transient transfection assays that the −270/−41 region of the Fli-1 gene displays promoter activity which is transactivated by Spi-1/PU.1. This promoter is strictly dependent on the integrity of two highly conserved ETS DNA binding sites that bind the Spi-1/PU.1 protein in vitro. Finally, we show that transfection of constitutive or inducible Fli-1 expression vectors in SFFV-transformed cells inhibits their erythroid differentiation induced by HMBA. Overall, these data indicate that Fli-1 is a target gene of the Spi-1/PU.1 transcription factor in SFFV-transformed cell lines. We further suggest that deregulated synthesis of Fli-1 may trigger a common mechanism contributing to erythroleukemia induced by either SFFV or F-MuLV.
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Lakhanpal, Gurpreet K., Laura M. Vecchiarelli-Federico, You-Jun Li, Jiu-Wei Cui, Monica L. Bailey, David E. Spaner, Daniel J. Dumont, Dwayne L. Barber, and Yaacov Ben-David. "The inositol phosphatase SHIP-1 is negatively regulated by Fli-1 and its loss accelerates leukemogenesis." Blood 116, no. 3 (July 22, 2010): 428–36. http://dx.doi.org/10.1182/blood-2009-10-250217.
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Abstract The activation of Fli-1, an Ets transcription factor, is the critical genetic event in Friend murine leukemia virus (F-MuLV)–induced erythroleukemia. Fli-1 overexpression leads to erythropoietin-dependent erythroblast proliferation, enhanced survival, and inhibition of terminal differentiation, through activation of the Ras pathway. However, the mechanism by which Fli-1 activates this signal transduction pathway has yet to be identified. Down-regulation of the Src homology 2 (SH2) domain-containing inositol-5-phosphatase-1 (SHIP-1) is associated with erythropoietin-stimulated erythroleukemic cells and correlates with increased proliferation of transformed cells. In this study, we have shown that F-MuLV–infected SHIP-1 knockout mice display accelerated erythroleukemia progression. In addition, RNA interference (RNAi)-mediated suppression of SHIP-1 in erythroleukemia cells activates the phosphatidylinositol 3-kinase (PI 3-K) and extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathways, blocks erythroid differentiation, accelerates erythropoietin-induced proliferation, and leads to PI 3-K–dependent Fli-1 up-regulation. Chromatin immunoprecipitation and luciferase assays confirmed that Fli-1 binds directly to an Ets DNA binding site within the SHIP-1 promoter and suppresses SHIP-1 transcription. These data provide evidence to suggest that SHIP-1 is a direct Fli-1 target, SHIP-1 and Fli-1 regulate each other in a negative feedback loop, and the suppression of SHIP-1 by Fli-1 plays an important role in the transformation of erythroid progenitors by F-MuLV.
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Mao, X., S. Miesfeldt, H. Yang, J. M. Leiden, and C. B. Thompson. "The FLI-1 and chimeric EWS-FLI-1 oncoproteins display similar DNA binding specificities." Journal of Biological Chemistry 269, no. 27 (July 1994): 18216–22. http://dx.doi.org/10.1016/s0021-9258(17)32437-7.
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Bailly, R. A., R. Bosselut, J. Zucman, F. Cormier, O. Delattre, M. Roussel, G. Thomas, and J. Ghysdael. "DNA-binding and transcriptional activation properties of the EWS-FLI-1 fusion protein resulting from the t(11;22) translocation in Ewing sarcoma." Molecular and Cellular Biology 14, no. 5 (May 1994): 3230–41. http://dx.doi.org/10.1128/mcb.14.5.3230.
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The 5' half of the EWS gene has recently been described to be fused to the 3' regions of genes encoding the DNA-binding domain of several transcriptional regulators, including ATF1, FLI-1, and ERG, in several human tumors. The most frequent occurrence of this situation results from the t(11;22)(q24;q12) chromosome translocation specific for Ewing sarcoma (ES) and related tumors which joins EWS sequences to the 3' half of FLI-1, which encodes a member of the Ets family of transcriptional regulators. We show here that this chimeric gene encodes an EWS-FLI-1 nuclear protein which binds DNA with the same sequence specificity as the wild-type parental FLI-1 protein. We further show that EWS-FLI-1 is an efficient sequence-specific transcriptional activator of model promoters containing FLI-1 (Ets)-binding sites, a property which is strictly dependent on the presence of its EWS domain. Comparison of the properties of the N-terminal activation domain of FLI-1 to those of the EWS domain of the fusion protein indicates that EWS-FLI-1 has altered transcriptional activation properties compared with FLI-1. These results suggest that EWS-FLI-1 contributes to the transformed phenotype of ES tumor cells by inducing the deregulated and/or unscheduled activation of genes normally responsive to FLI-1 or to other close members of the Ets family. ES and related tumors are characterized by an elevated level of c-myc expression. We show that EWS-FLI-1 is a transactivator of the c-myc promoter, suggesting that upregulation of c-myc expression is under control of EWS-FLI-1.
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Bailly, R. A., R. Bosselut, J. Zucman, F. Cormier, O. Delattre, M. Roussel, G. Thomas, and J. Ghysdael. "DNA-binding and transcriptional activation properties of the EWS-FLI-1 fusion protein resulting from the t(11;22) translocation in Ewing sarcoma." Molecular and Cellular Biology 14, no. 5 (May 1994): 3230–41. http://dx.doi.org/10.1128/mcb.14.5.3230-3241.1994.
Full textAbstract:
The 5' half of the EWS gene has recently been described to be fused to the 3' regions of genes encoding the DNA-binding domain of several transcriptional regulators, including ATF1, FLI-1, and ERG, in several human tumors. The most frequent occurrence of this situation results from the t(11;22)(q24;q12) chromosome translocation specific for Ewing sarcoma (ES) and related tumors which joins EWS sequences to the 3' half of FLI-1, which encodes a member of the Ets family of transcriptional regulators. We show here that this chimeric gene encodes an EWS-FLI-1 nuclear protein which binds DNA with the same sequence specificity as the wild-type parental FLI-1 protein. We further show that EWS-FLI-1 is an efficient sequence-specific transcriptional activator of model promoters containing FLI-1 (Ets)-binding sites, a property which is strictly dependent on the presence of its EWS domain. Comparison of the properties of the N-terminal activation domain of FLI-1 to those of the EWS domain of the fusion protein indicates that EWS-FLI-1 has altered transcriptional activation properties compared with FLI-1. These results suggest that EWS-FLI-1 contributes to the transformed phenotype of ES tumor cells by inducing the deregulated and/or unscheduled activation of genes normally responsive to FLI-1 or to other close members of the Ets family. ES and related tumors are characterized by an elevated level of c-myc expression. We show that EWS-FLI-1 is a transactivator of the c-myc promoter, suggesting that upregulation of c-myc expression is under control of EWS-FLI-1.
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Mélet, F., B. Motro, D. J. Rossi, L. Zhang, and A. Bernstein. "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." Molecular and Cellular Biology 16, no. 6 (June 1996): 2708–18. http://dx.doi.org/10.1128/mcb.16.6.2708.
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The proto-oncogene Fli-1 is a member of the ets family of transcription factor genes. Its activation by either chromosomal translocation or proviral insertion leads to Ewing's sarcoma in humans or erythroleukemia in mice, respectively, Fli-1 is preferentially expressed in hematopoietic and endothelial cells. This expression pattern resembled that of c-ets-1, another ets gene closely related and physically linked to Fli-1. We also generated a germ line mutation in Fli-1 by homologous recombination in embryonic stem cells. Homozygous mutant mice exhibit thymic hypocellularity which is not related to a defect in a specific subpopulation of thymocytes or to increased apoptosis, suggesting that Fli-1 is an important regulator of a prethymic T-cell progenitor. This phenotype was corrected by crossing the Fli-1 deficient mice expressing Fli-1 cDNA. Homozygous mutant mice remained susceptible to erythroleukemia induction by Friend murine leukemia virus, although the latency period was significantly increased. Surprisingly, the mutant Fli-1 allele was still a target for Friend murine leukemia virus integration, and leukemic spleens with a rearranged Fli-1 gene expressed a truncated Fli-1 protein that appears to arise from an internal translation initiation site and alternative splicing around the neo cassette used in the gene targeting. The fortuitous discovery of the mutant Fli-1 protein, revealed only as the result of the clonal expansion of leukemic cells harboring a rearranged Fli-1 gene, suggests caution in the interpretation of gene-targeting experiments that result in either no or only a subtle phenotypic alteration.
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Hu, Wei, Alana S. Philips, Juliana C. Kwok, Michael Eisbacher, and Beng H. Chong. "Identification of Nuclear Import and Export Signals within Fli-1: Roles of the Nuclear Import Signals in Fli-1-Dependent Activation of Megakaryocyte-Specific Promoters." Molecular and Cellular Biology 25, no. 8 (April 15, 2005): 3087–108. http://dx.doi.org/10.1128/mcb.25.8.3087-3108.2005.
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ABSTRACT The Ets factor Friend leukemia integration 1 (Fli-1) is an important regulator of megakaryocytic (Mk) differentiation. Here, we demonstrate two novel nuclear localization signals (NLSs) within Fli-1: one (NLS1) is located at the N terminus, and another (NLS2) is within the Ets domain. Nuclear accumulation of Fli-1 reflected the combined functional effects of the two discrete NLSs. Each NLS can independently direct nuclear transport of a carrier protein, with mutations within the NLSs affecting nuclear accumulation. NLS1 has a bipartite motif, whereas the NLS2 region contains a nonclassical NLS. Both NLSs bind importin alpha (IMPα) and IMPβ, with NLS1 and NLS2 being predominantly recognized by IMPα and IMPβ, respectively. Fli-1 also contains one nuclear export signal. Leptomycin B abolished its cytoplasmic accumulation, showing CRM1 dependency. We demonstrate that Ets domain binding to specific target DNA effectively blocks IMP binding, indicating that the targeted DNA binding plays a role in localizing Fli-1 to its destination and releasing IMPs for recycling back to the cytoplasm. Finally, by analyzing full-length Fli-1 carrying NLS1, NLS2, and combined NLS1-NLS2 mutations, we conclude that two functional NLSs exist in Fli-1 and that each NLS is sufficient to target Fli-1 to the nucleus for activation of Mk-specific genes.
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Song, Wei, Jiuwei Cui, Wei Li, Guanjun Wang, and Yan Li. "Expression of FLI-1 and the proliferation and survival of small cell lung cancer cells." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e18550-e18550. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e18550.
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e18550 Background: Small cell lung cancer (SCLC) exhibits aggressive behavior, rapid growth, early spread to distant sites. Over the last few decades, prognosis for patients with SCLC has changed little and there remains an critical need for evaluating novel agents. Here, we report that Fli-1 (Friend leukemia virus integration 1), a transcription factor and member of the Ets family, has an essential role in SCLC progression and may be a promising target for therapy. Methods: Immunohistochemical staining was used to investigate the expression level of Fli-1 in 25 patients with SCLC, including 12 patients in limited stage and 13 patients in extensive stage. The growth, apoptosis assay and molecular mechanism of Fli-1 in SCLC cell line (NCI-H446) was studied by down-regulating Fli-1 expression through RNA interference. Results: It was shown that expression level of Fli-1 was significantly up-regulated in SCLC tissues compared with adjacent tissues (p=0.0002). Its staining was found specifically in the nuclei of cancer cells. Expression level of Fli-1 was higher in extensive stage disease than that in limited stage disease (p=0.0045). Down-regulation of Fli-1 expression by RNA interference in NCI-H446 was found to strongly decrease cell growth, promote cell apoptosis and reduce metastasis. Importantly, when Fli-1 was down-regulated in NCI-H446, epidermal growth factor (EGF)-induced Akt activation was dramatically decreased. It was implied that Fli-1 was involved in the Akt regulation passway. It was also confirmed that the apoptosis induced by decrease of Fli-1 expression via down-regulation of its target regulation gene, bcl-2. Conclusions: The novel mechanistic insight into a critical role of Fli-1 in SCLC progression was shown in this study. Fli-1 overexpression promotes SCLC aggression partly via activating Akt phosphorylation. We propose that Fli-1 is a new powerful predictor for SCLC progression, and is also a new potential target for SCLC treatment.
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Starck, Joëlle, Nathalie Cohet, Colette Gonnet, Sandrine Sarrazin, Zina Doubeikovskaia, Alexandre Doubeikovski, Alexis Verger, Martine Duterque-Coquillaud, and François Morle. "Functional Cross-Antagonism between Transcription Factors FLI-1 and EKLF." Molecular and Cellular Biology 23, no. 4 (February 15, 2003): 1390–402. http://dx.doi.org/10.1128/mcb.23.4.1390-1402.2003.
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ABSTRACT FLI-1 is an ETS family transcription factor which is overexpressed in Friend erythroleukemia and contributes to the blockage of differentiation of erythroleukemic cells. We show here that FLI-1 represses the transcriptional activity of the β-globin gene promoter in MEL cells and interacts with two of its critical transactivators, GATA-1 and EKLF. Unexpectedly, FLI-1 enhances the stimulating activity of GATA-1 on a GATA-1-responsive promoter but represses that of EKLF on β-globin and an EKLF-responsive artificial promoters. This repressive effect of FLI-1 requires the ETS DNA binding domain and its association with either the N- or C-terminal domain, which themselves interact with EKLF but not with GATA-1. Furthermore, the FLI-1 ETS domain alone behaves as an autonomous repression domain when linked to the Gal4 DNA binding domain. Taken together, these data indicate that FLI-1 represses EKLF-dependent transcription due to the repression activity of its ETS domain and its indirect recruitment to erythroid promoters by protein-protein interaction with EKLF. Reciprocally, we also show that EKLF itself represses the FLI-1-dependent megakaryocytic GPIX gene promoter, thus further suggesting that functional cross-antagonism between FLI-1 and EKLF might be involved in the control of the erythrocytic versus megakaryocytic differentiation of bipotential progenitors.
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Zhang, L., A. Eddy, Y. T. Teng, M. Fritzler, M. Kluppel, F. Melet, and A. Bernstein. "An immunological renal disease in transgenic mice that overexpress Fli-1, a member of the ets family of transcription factor genes." Molecular and Cellular Biology 15, no. 12 (December 1995): 6961–70. http://dx.doi.org/10.1128/mcb.15.12.6961.
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The proto-oncogene Fli-1 is a member of the ets family of transcription factor genes. Its high expression in the thymus and spleen and the presence of DNA binding sites for Fli-1 in a number of lymphoid cell-specific gene suggest that Fli-1 is involved in the regulation of lymphopoiesis. Activation of the Fli-1 gene by either chromosomal translocation or viral insertion leads to Ewing's sarcoma in humans and erythroleukemia in mice, respectively. Thus, Fli-1 is normally involved in pathways involved in the regulation of cell growth and differentiation. We have generated H-2Kk-Fli-1 transgenic mice that overexpress Fli-1 in various mouse tissues, with the highest levels of Fli-1 protein in the thymus and spleen. These Fli-1 transgenic mice developed a high incidence of a progressive immunological renal disease and ultimately died of renal failure caused by tubulointerstitial nephritis and immune-complex glomerulonephritis. The incidences of renal disease correlated with the levels of Fli-1 protein in lymphoid tissues of transgenic lines. The hypergammaglobulinemia, splenomegaly, B-cell hyperplasia, accumulation of abnormal CD3+ B220+ T lymphoid cells and CD5+ B220+ B cells in peripheral lymphoid tissues, and detection of various autoantibodies in the sera of diseased Fli-1 transgenic mice suggested the involvement of an immune dysfunction in the pathogenesis of the renal disease. In addition, splenic B cells from transgenic mice exhibited increased proliferation and prolonged survival in vitro in response to mitogens. Taken together, these data suggest that overexpression or ectopic expression of Fli-1 perturbs normal lymphoid cell function and programmed cell death. Thus, H-2Kk-Fli-1 transgenic mice may serve as a murine model for autoimmune disease in humans, such as systemic lupus erythematosus.
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Masuya, Masahiro, Omar Moussa, Takanori Abe, Takao Deguchi, Tsukasa Higuchi, Yasuhiro Ebihara, Demetri D. Spyropoulos, Dennis K. Watson, and Makio Ogawa. "Dysregulation of granulocyte, erythrocyte, and NK cell lineages in Fli-1 gene–targeted mice." Blood 105, no. 1 (January 1, 2005): 95–102. http://dx.doi.org/10.1182/blood-2003-12-4345.
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Abstract Targeted disruption of the Friend leukemia integration 1 (Fli-1) proto-oncogene results in severe dysmegakaryopoiesis and embryonic lethality. We used morula-stage aggregation as a strategy to further clarify the hematopoietic defects of the Fli-1 gene-targeted mice. 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. Transplantation studies using sorted Fli-1 mutant cells produced similar findings. Clonal culture studies of bone marrow cells revealed increased numbers of granulocytic and early erythroid progenitors in the Fli-1+/- cells. The sorted Fli-1-/- bone marrow cells revealed specific down-regulation of CCAAT/enhancer binding protein-α (C/EBPα) and C/EBPϵ, and the receptors for granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF), consistent with their critical roles in granulopoiesis. Collectively, these observations suggest previously unknown physiologic roles for Fli-1 in granulocytic, erythroid, and NK cell proliferation and differentiation. Production of chimeras by morula-stage embryo aggregation is an effective way to unravel cell-autonomous hematopoietic defects in gene-targeted mice.
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Pang, Liyan, Xun Wang, Yuhuan Wang, Gerd Blobel, and Mortimer Poncz. "Maturation Stage-Specific Regulation of Megakaryocytic Genes by Pointed-Domain Ets Proteins." Blood 106, no. 11 (November 16, 2005): 1737. http://dx.doi.org/10.1182/blood.v106.11.1737.1737.
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Abstract The pointed-domain Ets transcription factor Fli-1 has a critical role during megakaryocyte-specific gene expression. Previously, we demonstrated that Fli-1 occupies the early megakaryocyte-specific gene αIIb in vivo. Moreover, our work suggested a mechanism for Fli-1 function by showing that Fli-1 facilitates GATA-1/FOG-1 dependent expression of the αIIb gene. However, studies by others with a targeted disruption of the Fli-1 gene in mice showed that while Fli-1 is essential for normal megakaryocyte maturation, αIIb mRNA levels were not significantly reduced in the resulting megakaryocytes, suggesting that a related Ets factor(s) might compensate for the loss of Fli-1. Here we show that the widely expressed pointed domain Ets protein GABPα specifically binds in vitro to Ets elements from two early megakaryocyte-specific genes, αIIb and c-mpl. Chromatin immunoprecipitation (ChIP) experiments using primary murine fetal liver-derived megakaryocytes reveal that GABPα associates with αIIb and c-mpl in vivo. Moreover, GABPα is capable of mediating GATA-1/FOG-1 synergy in the context of αIIb promoter constructs. These results suggest that GABPα contributes to megakaryocyte-restricted gene expression and is capable of at least partially compensating for the loss of Fli-1. However, loss of Fli-1 leads to a pronounced decrease in the expression of the late megakaryocyte-specific gene GPIX, indicating that compensation by GABPα is incomplete. Consistent with this observation, ChIP experiments fail to detect significant levels of GABPα at the regulatory region of GPIX while Fli-1 is readily detected there. Together, these results point to a model in which Fli-1 and GABPα serve overlapping, but distinct roles, during the development of megakaryocytes. GABPα may be important during early megakaryopoiesis, but Fli-1 exerting an essential role during late stages of maturation.
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Chan, D., T. J. Wilson, D. Xu, H. E. Cowdery, E. Sanij, P. J. Hertzog, and I. Kola. "Transformation induced by Ewing's sarcoma associated EWS/FLI-1 is suppressed by KRAB/FLI-1." British Journal of Cancer 88, no. 1 (January 2003): 137–45. http://dx.doi.org/10.1038/sj.bjc.6600669.
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Huang, Hui, Ming Yu, Tyler B. Moran, Nathan Tu, Thomas E. Akie, and Alan B. Cantor. "Differentiation-Dependent Interactions Between Runx-1 and Fli-1 during Megakaryocyte Development." Blood 112, no. 11 (November 16, 2008): 279. http://dx.doi.org/10.1182/blood.v112.11.279.279.
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Abstract The transcription factor Runx-1 is required for the ontogeny of all definitive hematopoiesis, and plays a specific role in megakaryopoiesis during later stages of development. Germline mutations in Runx-1 cause Familial Platelet Disorder with Propensity to Develop AML (FPD/AML), and acquired mutations occur in a subset of patients with myelodysplastic syndrome (MDS) and acute myelogenous leukemia. Although many of the reported Runx-1 mutations affect DNA binding and/or its interaction with the cofactor CBF-beta, other mutations occur outside of these binding regions and have unknown mechanistic effects. In this study, we purified Runx-1 containing multiprotein complexes from murine megakaryocytic cells in order to identify potential novel Runx-1 associated factors whose interaction may be altered by Runx-1 mutations. Here we report the identification of the key megakaryocyte ets transcription factor Fli- 1 as a direct Runx-1 binding partner. This interaction involves the negative regulatory DNA binding and activation domains of Runx-1 (amino acids 179–370), and a region around the Ets DNA binding region of Fli-1 (amino acids 281–361). The interaction is lost in the MDS- associated Y254X Runx-1 mutation. We also show that Runx-1 and Fli-1 co-occupy the c-mpl promoter in primary megakaryocytes and act synergistically in transcriptional reporter assays. Interestingly, the interaction between Runx-1 and Fli- 1 occurs in murine L8057 megakaryoblastic cells only after they have been induced to differentiate, even though both proteins are expressed abundantly in uninduced cells. The interaction correlates with assembly of a large multiprotein complex that also includes the key megakaryocyte transcription factor GATA-1 and its cofactor Friend of GATA-1 (FOG- 1) based on gel filtration chromatography experiments. Furthermore, we show that Fli-1 from this large complex lacks phosphorylation of a specific residue that is phosphorylated on non-complexed Fli-1. Mutation of this site to aspartic acid, which mimics constitutive phosphorylation, disrupts the interaction between Fli-1 and Runx-1 and abrogates their transcriptional synergy. We propose that dephosphorylation of Fli-1 is a key event in the transcriptional activation of megakaryocyte terminal maturation by facilitating the assembly of a RUNX-1/FLI-1/GATA-1/FOG-1 enhancesome complex. These findings have implications for the differentiation of other cell types where interactions between Runx and ets family proteins occur.
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Tsantili-Kakoulidou, Anna, Maria Chatzopoulou, and Vassilis J. Demopoulos. "Fraction Lipophilicity Index (FLI)." International Journal of Quantitative Structure-Property Relationships 4, no. 1 (January 2019): 41–66. http://dx.doi.org/10.4018/ijqspr.2019010104.
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Fraction lipophilicity index (FLI) was developed as a metric for assessing oral drug likeness of ionizable chemical entities, as a weighted combination of log P and log D according to equation: FLI = 2xlog P–log D. The dataset included basic and acidic oral drugs introduced worldwide from 1994-2013. Using MedChemDesigner for logP and logD calculations, a drug-like FLI range of 1-8 is defined, whereas ClogP leads to a broader FLI(C) range of 1-10. A comparison of FLI with Rule of 5 showed that oral drugs with a two fold violation were well accommodated within the specified FLI ranges. Calculations of FLI and FLI(C) for 41 drugs with poor/moderately absorption showed that 40% of them have values outside the suggested drug-like ranges, while a distinct gap in the FLI and FLI(C) space permits the recommendation of ‘safer' ranges: for bases between 5-8 and 5-10 for FLI and FLI(C), respectively, and for acids between 4-7. Application of FLI to a test set of investigational compounds placed all of them within the drug-like FLI/ FLI(C) range, while discriminating two out of three low permeable molecules.
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Torchia, Enrique C., Kelli Boyd, Jerold E. Rehg, Chunxu Qu, and Suzanne J. Baker. "EWS/FLI-1 Induces Rapid Onset of Myeloid/Erythroid Leukemia in Mice." Molecular and Cellular Biology 27, no. 22 (September 17, 2007): 7918–34. http://dx.doi.org/10.1128/mcb.00099-07.
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ABSTRACT EWS/FLI-1 is a chimeric oncogene generated by chromosomal translocation in Ewing tumors, a family of poorly differentiated pediatric tumors arising predominantly in bone but also in soft tissue. The fusion gene combines sequences encoding a strong transactivating domain from the EWS protein with the DNA binding domain of FLI-1, an ETS transcription factor. A related fusion, TLS/ERG, has been found in myeloid leukemia. To determine EWS/FLI-1 function in vivo, we engineered mice with Cre-inducible expression of EWS/FLI-1 from the ubiquitous Rosa26 locus. When crossed with Mx1-cre mice, Cre-mediated activation of EWS/FLI-1 resulted in the rapid development of myeloid/erythroid leukemia characterized by expansion of primitive mononuclear cells causing hepatomegaly, splenomegaly, severe anemia, and death. The disease could be transplanted serially into naïve recipients. Gene expression profiles of primary and transplanted animals were highly similar, suggesting that activation of EWS/FLI-1 was the primary event leading to disease in this model. The Cre-inducible EWS/FLI-1 mouse provides a novel model system to study the contribution of this oncogene to malignant disease in vivo.
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Bastian, L. Scot, Boguslaw A. Kwiatkowski, John Breininger, Susan Danner, and Gerald Roth. "Regulation of the Megakaryocytic Glycoprotein IX Promoter by the Oncogenic Ets Transcription Factor Fli-1." Blood 93, no. 8 (April 15, 1999): 2637–44. http://dx.doi.org/10.1182/blood.v93.8.2637.
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Abstract Glycoprotein (GP) IX is a subunit of the von Willebrand receptor, GPIb-V-IX, which mediates adhesion of platelets to the subendothelium of damaged blood vessels. Previous characterization of the GPIX promoter identified a functional Ets site that, when disrupted, reduced promoter activity. However, the Ets protein(s) that regulated GPIX promoter expression was unknown. In this study, transient cotransfection of several GPIX promoter/reporter constructs into 293T kidney fibroblasts with a Fli-1 expression vector shows that the oncogenic protein Fli-1 can transactivate the GPIX promoter when an intact GPIX Ets site is present. In addition, Fli-1 binding of the GPIX Ets site was identified in antibody supershift experiments in nuclear extracts derived from hematopoietic human erythroleukemia cells. Comparative studies showed that Fli-1 was also able to transactivate the GPIb and, to a lesser extent, the GPIIb promoter. Immunoblot analysis identified Fli-1 protein in lysates derived from platelets. In addition, expression of Fli-1 was identified immunohistochemically in megakaryocytes derived from CD34+ cells treated with the megakaryocyte differentiation and proliferation factor, thrombopoietin. These results suggest that Fli-1 is likely to regulate lineage-specific genes during megakaryocytopoiesis.
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Bastian, L. Scot, Boguslaw A. Kwiatkowski, John Breininger, Susan Danner, and Gerald Roth. "Regulation of the Megakaryocytic Glycoprotein IX Promoter by the Oncogenic Ets Transcription Factor Fli-1." Blood 93, no. 8 (April 15, 1999): 2637–44. http://dx.doi.org/10.1182/blood.v93.8.2637.408k20_2637_2644.
Full textAbstract:
Glycoprotein (GP) IX is a subunit of the von Willebrand receptor, GPIb-V-IX, which mediates adhesion of platelets to the subendothelium of damaged blood vessels. Previous characterization of the GPIX promoter identified a functional Ets site that, when disrupted, reduced promoter activity. However, the Ets protein(s) that regulated GPIX promoter expression was unknown. In this study, transient cotransfection of several GPIX promoter/reporter constructs into 293T kidney fibroblasts with a Fli-1 expression vector shows that the oncogenic protein Fli-1 can transactivate the GPIX promoter when an intact GPIX Ets site is present. In addition, Fli-1 binding of the GPIX Ets site was identified in antibody supershift experiments in nuclear extracts derived from hematopoietic human erythroleukemia cells. Comparative studies showed that Fli-1 was also able to transactivate the GPIb and, to a lesser extent, the GPIIb promoter. Immunoblot analysis identified Fli-1 protein in lysates derived from platelets. In addition, expression of Fli-1 was identified immunohistochemically in megakaryocytes derived from CD34+ cells treated with the megakaryocyte differentiation and proliferation factor, thrombopoietin. These results suggest that Fli-1 is likely to regulate lineage-specific genes during megakaryocytopoiesis.
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Quick, C. Matthew, Bruce R. Smoller, and Kim M. Hiatt. "Fli-1 expression in mycosis fungoides." Journal of Cutaneous Pathology 33, no. 9 (September 2006): 642–45. http://dx.doi.org/10.1111/j.1600-0560.2006.00535.x.
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Braun, B. S., R. Frieden, S. L. Lessnick, W. A. May, and C. T. Denny. "Identification of target genes for the Ewing's sarcoma EWS/FLI fusion protein by representational difference analysis." Molecular and Cellular Biology 15, no. 8 (August 1995): 4623–30. http://dx.doi.org/10.1128/mcb.15.8.4623.
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The EWS/FLI-1 fusion gene results from the 11;22 chromosomal translocation in Ewing's sarcoma. The product of the gene is one of a growing number of structurally altered transcription factors implicated in oncogenesis. We have employed a subtractive cloning strategy of representational difference analysis in conjunction with a model transformation system to identify genes transcribed in response to EWS/FLI. We have characterized eight transcripts that are dependent on EWS/FLI for expression and two transcripts that are repressed in response to EWS/FLI. Three of the former were identified by sequence analysis as stromelysin 1, a murine homolog of cytochrome P-450 F1 and cytokeratin 15. Stromelysin 1 is induced rapidly after expression of EWS/FLI, suggesting that the stromelysin 1 gene may be a direct target gene of EWS/FLI. These results demonstrate that expression of EWS/FLI leads to significant changes in the transcription of specific genes and that these effects are at least partially distinct from those caused by expression of germ line FLI-1. The representational difference analysis technique can potentially be applied to investigate transformation pathways activated by a broad array of genes in different tumor systems.
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Eliazer, Susan, Jeffrey Spencer, Dan Ye, Eric Olson, and Robert L. Ilaria. "Alteration of Mesodermal Cell Differentiation by EWS/FLI-1, the Oncogene Implicated in Ewing's Sarcoma." Molecular and Cellular Biology 23, no. 2 (January 15, 2003): 482–92. http://dx.doi.org/10.1128/mcb.23.2.482-492.2003.
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ABSTRACT The chimeric fusion gene EWS/FLI-1 is detected in most cases of Ewing's sarcoma (ES), the second most common malignant bone tumor of childhood. Although 80% of ES tumors develop in skeletal sites, the remainder can arise in almost any soft tissue location. The lineage of the cell developing the EWS/FLI-1 gene fusion has not been fully characterized but is generally considered to be of either mesenchymal or neural crest origin. To study this oncogene in a conceptually relevant target cell, EWS/FLI-1 was introduced into the murine cell line C2C12, a myoblast cell line capable of differentiation into muscle, bone, or fat. In this cellular context, EWS/FLI-1 profoundly inhibited the myogenic differentiation program. The block in C2C12 myogenic differentiation required the nuclear localization and DNA-binding functions of EWS/FLI-1 and was mediated by transcriptional and posttranscriptional suppression of the myogenic transcription factors MyoD and myogenin. Interestingly, C2C12-EWS/FLI-1 cells constitutively expressed alkaline phosphatase, a bone lineage marker, and were alkaline phosphatase positive by histochemistry but showed no other evidence of bone lineage commitment. Consistent with recent findings in human ES tumor cell lines, C2C12-EWS/FLI-1 cells constitutively expressed cyclin D1 and demonstrated decreased expression of the cell cycle regulator p21cip1, even under differentiation conditions and at confluent density. This C2C12-EWS/FLI-1 cell model may assist in the identification of novel differentially expressed genes relevant to ES and provide further insight into the cell(s) of origin developing ES-associated genetic fusions.
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Bouilloux, Fabrice, Gaëtan Juban, Nathalie Cohet, Dorothée Buet, Boris Guyot, William Vainchenker, Fawzia Louache, and François Morlé. "EKLF restricts megakaryocytic differentiation at the benefit of erythrocytic differentiation." Blood 112, no. 3 (August 1, 2008): 576–84. http://dx.doi.org/10.1182/blood-2007-07-098996.
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Abstract Previous observations suggested that functional antagonism between FLI-1 and EKLF might be involved in the commitment toward erythrocytic or megakaryocytic differentiation. We show here, using inducible shRNA expression, that EKLF knockdown in mouse erythroleukemia (MEL) cells decreases erythrocytic and increases megakaryocytic as well as Fli-1 gene expression. Chromatin immunoprecipitation analyses revealed that the increase in megakaryocytic gene expression is associated with a marked increase in RNA pol II and FLI-1 occupancy at their promoters, albeit FLI-1 protein levels are only minimally affected. Similarly, we show that human CD34+ progenitors infected with shRNA lentivirus allowing EKLF knockdown generate an increased number of differentiated megakaryocytic cells associated with increased levels of megakaryocytic and Fli-1 gene transcripts. Single-cell progeny analysis of a cell population enriched in bipotent progenitors revealed that EKLF knockdown increases the number of megakaryocytic at the expense of erythrocytic colonies. Taken together, these data indicate that EKLF restricts megakaryocytic differentiation to the benefit of erythrocytic differentiation and suggest that this might be at least partially mediated by the inhibition of FLI-1 recruitment to megakaryocytic and Fli-1 gene promoters.
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Neuwirtova, Radana, Ota Fuchs, Dana Provaznikova, Jaroslav Cermak, Magda Siskova, Anna Jonasova, and Kyra Michalova. "Fli-1 and EKLF Gene Expression in Patients with MDS 5q- Syndrome." Blood 114, no. 22 (November 20, 2009): 2788. http://dx.doi.org/10.1182/blood.v114.22.2788.2788.
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Abstract Abstract 2788 Poster Board II-764 Introduction. Patients with MDS-5q- syndrome have macrocytic anemia often with hypoplastic erythropoiesis and on the contrary thrombocythemia with effective though dysplastic megakaryopoiesis. Megakaryocytes and erythroid cells are thought to share a common progenitor MEP (T.P.McDonald et al., Exp. Hematology 1993). There are two key transcription factors which together with other transcription factors and relevant cytokines and receptors determine the hemopoietic differentiation of the common stem cell: erythroid Krüppel-like factor (EKLF) for erythroid lineage and Friend leukemia virus integration 1 (FLi-1) for megakaryopoiesis (Pilar Frontelo et al., Blood 2007; G.A.Blobel, Blood 2007; F.Bouilloux et al., Blood 2008). There is functional cross antagonism between FLi-1 and EKLF (J.Starck et al., Mol. Cel. Biology 2003). FLi-1 is active only if dephosphorylated (H.Huang et al., ASH Abstracts 2008). The question is whether both factors play any role in 5q- syndrome. Methods. FLi-1 and EKLF gene expressions were determined in mononuclear cells isolated from the whole blood or bone marrow using Ficoll-Paque PLUS. Expression of both factors was measured by quantitative real-time PCR. RT-PCR products were verified by electrophoresis and direct sequencing. The assays were performed for sample in duplicate. Glyceraldehyd-3-phosphate dehydrogenase (GAPDH), FLi-1 and EKLF were amplified in 25 μl reaction mixture containing 12.5 μl SYBR Green JumpStart Taq Ready Mix, 2.5 μl 2 μM FLi-1 or EKLF forward and reverse primers, 0,25 μl internal reference dye and 1 μl cDNA. Relative levels of FLi-1 and EKLF mRNAs were calculated to the level of housekeeping GAPDH mRNA. Results. FLi-1 and EKLF were measured in blood mononuclear cells of 8 patients fulfilling all criterias of 5q- syndrome. FLi1mRNA/GAPDHmRNA was higher in all samples, average value was 0.0930 (0.0242-0.4274) compared to control value 0.0194. FLi1mRNA/GAPDHmRNA in bone marrow mononuclear cells of 7 patients with 5q- syndrome was higher in all samples but one. The average value was 0.0827 (0.0070-0.2554) compared to healthy controls 0.0044. EKLF gives very low values in the majority of patients′ blood and bone marrow samples as well as in healthy controls. The evaluation is therefore less reliable then FLi-1 assessment. EKLFmRNA/GAPDHmRNA in blood was 0.0004 (0.0-0.0023) compared to the control 0.0222. The results of EKLF in 5 bone marrow samples are inconsistent. Three are lower than the control (0.0068), 1 of remaining 2 samples is extremely high (0.3491). It is interesting that this patient is the only one who responded to erythropoietin and is transfusion independent. Summary. Our preliminary results with FLi-1 and EKLF gene expression measurement are in agreement with expected findings: increased FLi-1 expression corresponds to thrombocytemia in 5q- syndrome patients and expression of EKLF, lower than in controls would correspond to anemia in these patients. However, EKLF values are less reliable because of very low values in patients as well as in controls and because of inconsistent results in bone marrow samples. We prepare to follow both factors in 5q- patients after the treatment with lenalidomide. Lenalidomide improves anemia in 5q- syndrome patients and temporarily causes decrease of thrombocytes (A.List et al., N.Engl.J.Med. 2005, 2006). Inhibition of phosphatases by lenalidomide (S.Wei et al., Proc.Natl.Acad.Sci.USA 2009) can stop FLi-1 dephosphorylation which leads to FLi-1 inactivation. Hypotetically inactive FLi-1 would enable EKLF to induce MEP into erythroid lineage. Supported by MSM 0021620808 Disclosures: No relevant conflicts of interest to declare.
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Sato, Shuzo, Xian K. Zhang, Jumpei Temmoku, Yuya Fujita, Naoki Matsuoka, Makiko Yashiro-Furuya, Tomoyuki Asano, Hiroko Kobayashi, Hiroshi Watanabe, and Kiyoshi Migita. "Ets Family Transcription Factor Fli-1 Promotes Leukocyte Recruitment and Production of IL-17A in the MRL/Lpr Mouse Model of Lupus Nephritis." Cells 9, no. 3 (March 14, 2020): 714. http://dx.doi.org/10.3390/cells9030714.
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The transcription factor Friend leukemia integration 1 (Fli-1) regulates the expression of numerous cytokines and chemokines and alters the progression of lupus nephritis in humans and in the MRL/MpJ-Faslpr (MRL/lpr) mouse model. Th17-mediated immune responses are notably important as they promote ongoing inflammation. The purpose of this study is to determine the impact of Fli-1 on expression of interleukin-17A (IL-17A) and the infiltration of immune cells into the kidney. IL-17A concentrations were measured by ELISA in sera collected from MRL/lpr Fli-1-heterozygotes (Fli-1+/−) and MRL/lpr Fli-1+/+ control littermates. Expression of IL-17A and related proinflammatory mediators was measured by real-time polymerase chain reaction (RT-PCR). Immunofluorescence staining was performed on renal tissue from MRL/lpr Fli-1+/− and control littermates using anti-CD3, anti-CD4, and anti-IL-17A antibodies to detect Th17 cells and anti-CCL20 and anti-CD11b antibodies to identify CCL20+ monocytes. The expression of IL-17A in renal tissue was significantly reduced; this was accompanied by decreases in expression of IL-6, signal transducer and activator of transcription 3 (STAT3), and IL-1β. Likewise, we detected fewer CD3+IL-17+ and CD4+IL-17+ cells in renal tissue of MLR/lpr Fli-1+/− mice and significantly fewer CCL20+CD11b+ monocytes. In conclusion, partial deletion of Fli-1 has a profound impact on IL-17A expression and on renal histopathology in the MRL/lpr mouse.
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Tabe, Yoko, Linhua Jin, Yasuhito Hatanaka, Takashi Miida, Steven M. Kornblau, Michael Andreeff, and Marina Konopleva. "TGF-β1 Supports Leukemia Cell Survival Via Negative Regulation of FLI-1 Transcription Factor, ERK Inactivation and MMP-1 Secretion." Blood 120, no. 21 (November 16, 2012): 3543. http://dx.doi.org/10.1182/blood.v120.21.3543.3543.
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Abstract Abstract 3543 Transforming growth factor β (TGF-β) is an essential regulator of cell proliferation, survival, and apoptosis, depending on the cellular context. We have previously reported pro-survival effects of TGF-β1 in myelo-monocytic leukemia cells (Xu et al., Br J Haematol.2008) and the anti-leukemic effects of action of TGF-β neutralizing antibody under TGF-β abundant and hypoxic bone marrow (BM) microenvironment (ASH, 2012). Friend leukemia virus integration 1 (FLI-1), a member of Ets transcriptional factors, plays a pivotal role in the regulation of extracellular matrix (ECM) genes, and is known to be negatively regulated through TGF-β1-dependent acetylation. We have recently reported that abnormal (high or low) expression of FLI-1 protein analyzed by reverse phase protein arrays is associated with inferior remission duration and reduced survival (Kornblau et al., Blood, 2011). Notably, among 195 proteins tested, FLI-1 expression correlated most with SMAD4, the common mediator in a family of SMAD proteins involved in TGFβ signaling. In this study, we investigated the molecular interactions between TGF-β1 and FLI-1 in AML cells and its functional role in TGF-β-mediated survival. In four AML cell lines, MV4;11, U937, NB4, and OCI-AML3, recombinant TGF-β1 (2ng/mL) induced the TGF-β downstream signaling targets plasminogen activator inhibitor-1 (PAI-1, mRNA) and/or Smad2 phosphorylation, which was reversed by anti-TGF-β neutralizing antibody 1D11 (Genzyme). No consistent change of Smad4 expression was observed in TGF-β1 treated cells. Treatment with rhTGF-β1 inhibited serum starvation-induced apoptosis in MV4;11, U937 and NB4, but not in OCI-AML3 cells. The anti-apoptotic effect of TGF-β1 was associated with G0/G1 cell cycle arrest, which was effectively reversed by anti-TGF-β antibody 1D11. In MV4;11, U937 and NB4 cells, in which rhTGF-β1 promoted cell survival, rhTGF-β1 downregulated expression levels of FLI-1 mRNA and/or protein. However, FLI-1 was upregulated by rhTGF-β1 in OCI-AML3 cells. Since FLI-1 activation is known to cause cell proliferation associated with Ras pathway activation, we investigated MAPK signaling downstream of Ras. Changes in ERK phosphorylation levels after rhTGF-β1 treatment were fully concordant with FLI-1, whereby phospho-ERK was downregulated in MV4;11, U937, and NB4 cells, and upregulated in OCI-AML3 cells. These effects were reversed by anti-TGF-β antibody 1D11. In turn, rhTGF-β1 induced Matrix metalloproteinase-1 (MMP-1) mRNA which inversely correlated with FLI-1 expression. (U937; 6.9 fold increase, OCI-AML3; 3.1 fold decrease). It has been reported that ERK signaling upregulates MMP-1 expression, and that FLI-1 downregulates MMP-1 promoter activity in human fibroblasts. MMP-1, being responsible for degradation of collagenous proteins of ECM, correlates with poor prognosis in leukemia. We also observed that rhTGF-β1 induced significant upregulation of anti-apoptotic Bcl-2 in MV4;11, U937, and NB4 cells, but not in OCI-AML3 cells. In summary, TGF-β-induced FLI-1 downregulation and ERK inactivation may be implicated in pathological matrix remodeling via oncogenic MMP-1 transcription in TGF-β abundant BM microenvironment. These findings suggest that FLI-1 and MMP-1 contribute to chemoresistance and poor outcomes in AML and represent potentially targetable molecular aberrations in AML. Disclosures: No relevant conflicts of interest to declare.
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Rajesh, Yetirajam, Angana Biswas, Utkarsh Kumar, Indranil Banerjee, Subhayan Das, Santanu Maji, Swadesh K. Das, et al. "Lumefantrine, an antimalarial drug, reverses radiation and temozolomide resistance in glioblastoma." Proceedings of the National Academy of Sciences 117, no. 22 (May 14, 2020): 12324–31. http://dx.doi.org/10.1073/pnas.1921531117.
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Glioblastoma multiforme (GBM) is an aggressive cancer without currently effective therapies. Radiation and temozolomide (radio/TMZ) resistance are major contributors to cancer recurrence and failed GBM therapy. Heat shock proteins (HSPs), through regulation of extracellular matrix (ECM) remodeling and epithelial mesenchymal transition (EMT), provide mechanistic pathways contributing to the development of GBM and radio/TMZ-resistant GBM. The Friend leukemia integration 1 (Fli-1) signaling network has been implicated in oncogenesis in GBM, making it an appealing target for advancing novel therapeutics. Fli-1 is linked to oncogenic transformation with up-regulation in radio/TMZ-resistant GBM, transcriptionally regulating HSPB1. This link led us to search for targeted molecules that inhibit Fli-1. Expression screening for Fli-1 inhibitors identified lumefantrine, an antimalarial drug, as a probable Fli-1 inhibitor. Docking and isothermal calorimetry titration confirmed interaction between lumefantrine and Fli-1. Lumefantrine promoted growth suppression and apoptosis in vitro in parental and radio/TMZ-resistant GBM and inhibited tumor growth without toxicity in vivo in U87MG GBM and radio/TMZ-resistant GBM orthotopic tumor models. These data reveal that lumefantrine, an FDA-approved drug, represents a potential GBM therapeutic that functions through inhibition of the Fli-1/HSPB1/EMT/ECM remodeling protein networks.
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Tamir, Ami, Jeff Howard, Rachel R. Higgins, You-Jun Li, Lloyd Berger, Eldad Zacksenhaus, Marciano Reis, and Yaacov Ben-David. "Fli-1, an Ets-Related Transcription Factor, Regulates Erythropoietin-Induced Erythroid Proliferation and Differentiation: Evidence for Direct Transcriptional Repression of the Rb Gene during Differentiation." Molecular and Cellular Biology 19, no. 6 (June 1, 1999): 4452–64. http://dx.doi.org/10.1128/mcb.19.6.4452.
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ABSTRACT Erythropoietin (Epo) is a major regulator of erythropoiesis that alters the survival, proliferation, and differentiation of erythroid progenitor cells. The mechanism by which these events are regulated has not yet been determined. Using HB60, a newly established erythroblastic cell line, we show here that Epo-induced terminal erythroid differentiation is associated with a transient downregulation in the expression of the Ets-related transcription factor Fli-1. Constitutive expression of Fli-1 in HB60 cells, similar to retroviral insertional activation of Fli-1 observed in Friend murine leukemia virus (F-MuLV)-induced erythroleukemia, blocks Epo-induced differentiation while promoting Epo-induced proliferation. These results suggest that Fli-1 modulates the response of erythroid cells to Epo. To understand the mechanism by which Fli-1 regulates erythropoiesis, we searched for downstream target genes whose expression is regulated by this transcription factor. Here we show that the retinoblastoma (Rb) gene, which was previously shown to be involved in the development of mature erythrocytes, contains a Fli-1 consensus binding site within its promoter. Fli-1 binds to this cryptic Ets consensus site within the Rb promoter and transcriptionally represses Rb expression. Both the expression level and the phosphorylation status of Rb are consistent with the response of HB60 cells to Epo-induced terminal differentiation. We suggest that the negative regulation ofRb by Fli-1 could be one of the critical determinants in erythroid progenitor cell differentiation that is specifically deregulated during F-MuLV-induced erythroleukemia.
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Prieur, Alexandre, Franck Tirode, Pinchas Cohen, and Olivier Delattre. "EWS/FLI-1 Silencing and Gene Profiling of Ewing Cells Reveal Downstream Oncogenic Pathways and a Crucial Role for Repression of Insulin-Like Growth Factor Binding Protein 3." Molecular and Cellular Biology 24, no. 16 (August 15, 2004): 7275–83. http://dx.doi.org/10.1128/mcb.24.16.7275-7283.2004.
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ABSTRACT Ewing tumors are characterized by abnormal transcription factors resulting from the oncogenic fusion of EWS with members of the ETS family, most commonly FLI-1. RNA interference targeted to the junction between EWS and FLI-1 sequences was used to inactivate the EWS/FLI-1 fusion gene in Ewing cells and to explore the resulting phenotype and alteration of the gene expression profile. Loss of expression of EWS/FLI-1 resulted in the complete arrest of growth and was associated with a dramatic increase in the number of apoptotic cells. Gene profiling of Ewing cells in which the EWS/FLI-1 fusion gene had been inactivated identified downstream targets which could be grouped in two major functional clusters related to extracellular matrix structure or remodeling and regulation of signal transduction pathways. Among these targets, the insulin-like growth factor binding protein 3 gene (IGFBP-3), a major regulator of insulin-like growth factor 1 (IGF-1) proliferation and survival signaling, was strongly induced upon treating Ewing cells with EWS/FLI-1-specific small interfering RNAs. We show that EWS/FLI-1 can bind the IGFBP-3 promoter in vitro and in vivo and can repress its activity. Moreover, IGFBP-3 silencing can partially rescue the apoptotic phenotype caused by EWS/FLI-1 inactivation. Finally, IGFBP-3-induced Ewing cell apoptosis relies on both IGF-1-dependent and -independent pathways. These findings therefore identify the repression of IGFBP-3 as a key event in the development of Ewing's sarcoma.
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Schutt, Steven, Yongxia Wu, Anusara Daenthanasanmak, David Bastian, Carole Wilson, Lynn Schnapp, Xian Zhang, et al. "2050 Identifying the role and immunobiological mechanisms of Fli-1 mediated pathogenicity in graft Versus host disease." Journal of Clinical and Translational Science 2, S1 (June 2018): 14–15. http://dx.doi.org/10.1017/cts.2018.83.
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OBJECTIVES/SPECIFIC AIMS: Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a curative procedure for hematological malignancies. Chronic graft Versus host disease (cGVHD) is a lethal complication that often develops after allo-HCT. Fli-1 is an aberrantly expressed protein in cancers including erythroleukemia and melanoma, while being implicated in pathogenesis of systemic lupus in mice and humans, a disease with marked similarity to cGVHD. METHODS/STUDY POPULATION: cGVHD was induced using hematopoietic cells from conditional knock-out mice deficient for the fli-1 gene specifically on T cells and progression of cGVHD in murine allo-HCT recipients was monitored using a clinical scoring system, and changes in activation status of hematopoietic cell populations were quantified using flow cytometry. RESULTS/ANTICIPATED RESULTS: Recipients transplanted with fli-1 deficient T cells exhibited reduced cGVHD clinical scores compared with littermate wild-type controls. Donor-grafts containing fli-1 deficient T cells were associated with restrained T-cell responses including reduced Interferon-y cytokine production, PD-1 expression, and differentiation into follicular helper T cells. fli-1 T-cell deficient donor-grafts also improved donor B-cell reconstitution and reduced plasma cells in allo-HCT recipients relative to littermate wild-type control donor-graft recipients. DISCUSSION/SIGNIFICANCE OF IMPACT: Thus, inhibiting Fli-1 represents a promising therapeutic strategy for the goal of preventing cGVHD after allo-HCT while also directly targeting cancers which aberrantly express Fli-1.
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Zhang, Ye, Qing Shi, Xiwen Li, and Chunlin Xia. "Fasciculation and Elongation Protein Zeta-1 Expression in Reactive Astrocytes in a Rat Model of Frontal Lobe Injury." Journal of Neuropathology & Experimental Neurology 79, no. 2 (November 27, 2019): 194–208. http://dx.doi.org/10.1093/jnen/nlz113.
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Abstract There are reports that depression induced by frontal lobe injury (FLI) has a devastating effect on human mental health. We previously reported that fasciculation and elongation protein zeta-1 (FEZ1) was essential for astrocytic protection of dopamine neurons. Studies of glutamate-glutamine cycle in mental illness have been reported, whereas not from the perspective of astrocytes. This study was designed to investigate the roles of astrocytic FEZ1 and glutamate-glutamine cycle after FLI. A model of FLI was established by inserting a blade into the right frontal lobe of rats. Behavioral tests were used to observe the behavioral changes of FLI rats. Neuropathologic examinations, including immunohistochemistry, were conducted. Behavioral tests showed that FLI decreased exploratory activity. Western blot analysis revealed that the expression of astroglial proteins overall decreased in the initial injury stage, as well as FEZ1. Immunohistochemistry showed a shift of FEZ1 localization from neurons in sham-lesioned rats to astrocytes in FLI rats, and showed the expression profile of glutamate transporter 1 and glutamine synthetase (GS) was consistent with Western blot observation. Our results indicate that astrocytic FEZ1 and glutamate-glutamine cycle dysfunction may be involved in the pathogenesis of depression after FLI.
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Elzi, David J., Meihua Song, Peter J. Houghton, Yidong Chen, and Yuzuru Shiio. "The role of FLI-1-EWS, a fusion gene reciprocal to EWS-FLI-1, in Ewing sarcoma." Genes & Cancer 6, no. 11-12 (November 7, 2015): 452–61. http://dx.doi.org/10.18632/genesandcancer.86.
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Elkareh, Jihad, Sankaridrug M. Periyasamy, Amjad Shidyak, Sandeep Vetteth, Jeremy Schroeder, Vanamala Raju, Imad M. Hariri, et al. "Marinobufagenin induces increases in procollagen expression in a process involving protein kinase C and Fli-1: implications for uremic cardiomyopathy." American Journal of Physiology-Renal Physiology 296, no. 5 (May 2009): F1219—F1226. http://dx.doi.org/10.1152/ajprenal.90710.2008.
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The cardiotonic steroid marinobufagenin (MBG) has been implicated in the pathogenesis of experimental uremic cardiomyopathy, which is characterized by progressive cardiac fibrosis. We examined whether the transcription factor Friend leukemia integration-1 (Fli-1) might be involved in this process. Fli-1-knockdown mice demonstrated greater cardiac collagen-1 expression and fibrosis compared with wild-type mice; both developed increased cardiac collagen expression and fibrosis after 5/6 nephrectomy. There was a strong inverse relationship between the expressions of Fli-1 and procollagen in primary culture of rat cardiac and human dermal fibroblasts as well as a cell line derived from renal fibroblasts and MBG-induced decreases in nuclear Fli-1 as well as increases in procollagen-1 expression in these cells. Transfection of a Fli-1 expression vector prevented increased procollagen-1 expression from MBG. MBG exposure induced a rapid translocation of the δ-isoform of protein kinase C (PKCδ) to the nucleus. This translocation was prevented by pharmacological inhibition of phospholipase C, and MBG-induced increases in procollagen-1 expression were prevented with a PKCδ- but not a PKCα-specific inhibitor. Finally, immunoprecipitation studies strongly suggest that MBG induced phosphorylation of Fli-1. We feel these data support a causal relationship with MBG-induced translocation of PKCδ, which results in phosphorylation of as well as decreases in nuclear Fli-1 expression, which, in turn, leads to increases in collagen production. Should these findings be confirmed, we speculate that this pathway may represent a therapeutic target for uremic cardiomyopathy as well as other conditions associated with excessive fibrosis.
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Lebigot, Ingrid, Paola Gardellin, Laurent Lefebvre, Hartmut Beug, Jacques Ghysdael, and Christine Tran Quang. "Up-regulation of SLAP in FLI-1-transformed erythroblasts interferes with EpoR signaling." Blood 102, no. 13 (December 15, 2003): 4555–62. http://dx.doi.org/10.1182/blood-2003-06-2077.
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Abstract Rearrangement of the FLI-1 locus and ensuing overexpression of FLI-1 protein is an early event in Friend murine leukemia virus (F-MuLV)-induced erythroleukemia. When overexpressed in primary erythroblasts, FLI-1 converts erythropoietin (Epo)-induced terminal differentiation into a proliferative response. We found that SLAP, a gene encoding a recently described negative regulator of T-cell antigen receptor function during thymocyte development, is up-regulated both at the RNA and protein levels in FLI-1-transformed erythroblasts. Src-like adaptor protein (SLAP) was found in a specific complex with erythropoietin receptor (EpoR), a cytokine receptor essential to erythroid differentiation. Constitutive expression of SLAP severely impairs hemoglobinization and late survival during Epo-induced terminal differentiation of erythroblasts. This impairment is associated with the specific inhibition of several critical Epo-dependent signaling events, including signal transducer and activator of transcription 5 (STAT5) activation and up-regulation of the expression of the antiapoptotic BCL-X gene. Our data support a model by which FLI-1 inhibits normal erythroid differentiation through the deregulation of genes encoding adaptors/effectors that modify the signaling output of cytokine receptors normally required for terminal differentiation. (Blood. 2003; 102:4555-4562)
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Sarrazin, S., J. Starck, and F. Morlé. "Télescopage des ribosomes sur l'ARNm Fli-1." médecine/sciences 16, no. 8-9 (2000): 981. http://dx.doi.org/10.4267/10608/1770.
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Ramani, Nisha, Phyu P. Aung, Wen-Jen Hwu, Priyadharsini Nagarajan, Michael T. Tetzlaff, Johnathan L. Curry, Doina Ivan, Victor G. Prieto, and Carlos A. Torres-Cabala. "Aberrant expression of FLI-1 in melanoma." Journal of Cutaneous Pathology 44, no. 9 (July 10, 2017): 790–93. http://dx.doi.org/10.1111/cup.12979.
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Folpe, Andrew L., Charles E. Hill, David M. Parham, Patricia A. O'Shea, and Sharon W. Weiss. "Immunohistochemical Detection of FLI-1 Protein Expression." American Journal of Surgical Pathology 24, no. 12 (December 2000): 1657–62. http://dx.doi.org/10.1097/00000478-200012000-00010.
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Lesault, I. "Direct regulation of BCL-2 by FLI-1 is involved in the survival of FLI-1-transformed erythroblasts." EMBO Journal 21, no. 4 (February 15, 2002): 694–703. http://dx.doi.org/10.1093/emboj/21.4.694.
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Van Dijk, G., T. E. Thiele, J. C. Donahey, L. A. Campfield, F. J. Smith, P. Burn, I. L. Bernstein, S. C. Woods, and R. J. Seeley. "Central infusions of leptin and GLP-1-(7-36) amide differentially stimulate c-FLI in the rat brain." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 271, no. 4 (October 1, 1996): R1096—R1100. http://dx.doi.org/10.1152/ajpregu.1996.271.4.r1096.
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Recently, glucagon-like peptide-1-(7-36) amide (GLP-1) and leptin have been implicated in the regulation of food intake. In the present study, we compared the effects of third ventricular administration (i3vt) of leptin (3.5 micrograms) and GLP-1 (10.0 micrograms) on short-term food intake and c-Fos-like immunoreactivity (c-FLI) in hypothalamic, limbic, and hindbrain areas in the rat. Relative to controls, infusion of leptin or GLP-1 (3 h before lights off) significantly reduced food intake over the first 2 h in the dark phase (53 and 63%, respectively). In different rats, infusion of leptin or GLP-1 elevated c-FLI in the paraventricular hypothalamus and central amygdala. Furthermore, leptin selectively elevated c-FLI in the dorsomedial hypothalamus, whereas GLP-1 selectively elevated c-FLI in the nucleus of the solitary tract, area postrema, lateral parabrachial nucleus, and arcuate hypothalamic nucleus. The fact that most of the c-FLI after leptin or GLP-1 administration was observed in separate regions within the central nervous system (CNS) suggests different roles for leptin and GLP-1 in the CNS regulation of food intake and body weight.
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Peterlin, Pierre, Joelle Gaschet, Thierry Guillaume, Alice Garnier, Marion Eveillard, Amandine Le Bourgeois, Michel Cherel, et al. "Fms-like Tyrosine Kinase 3 Ligand Concentration Kinetic Profile during Induction Is Strongly Predictive of Survivals in AML: Results of the FLAM/Flal Study." Blood 132, Supplement 1 (November 29, 2018): 1484. http://dx.doi.org/10.1182/blood-2018-99-111694.
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Abstract The cytokine Fms-like tyrosine kinase 3 ligand (FL) is a key regulator of hematopoiesis. In a previous Phase 1 study testing a radioimmunotherapy regimen for relapsed/refractory acute lymphoblastic leukemia (ALL), responders showed increased soluble FL serum concentration (sFLc) after salvage regimen (Chevallier, Lancet Haematol., 2015). This prospective monocentric study (ClinicalTrials.gov NCT02693899) aimed to assess the impact of sFLc in ALL and acute myeloid leukemia (AML) patients treated according to standard-of-care intensive first-line chemotherapy regimens. Serum samples were collected on days 1, 8, 15, 22 of induction, at days 1, 8, 15 of each intensive consolidation or day 1 of each non intensive consolidation when appropriate, frozen-stored then tested by ELISA (DY308, R&D Systems, Minneapolis, MN). The following outcomes were considered to assess the impact of sFLc: refractory status after induction (≥5% bone marrow blasts or persistent aplasia >45 days), morphologic, immunophenotypic, cytogenetic or molecular relapses, event-free (EFS) and overall survival (OS). All patients provided informed consent. Between May 2016 and January 2018, 80 patients were included. Data were ultimately available for 16 ALL and 62 AML patients. A total of 579 samples were assayed. Analysis of the results disclosed 3 sFLc kinetic profiles during induction i) sustained increase from days 1 to 22 (FLI group), ii) increase from days 1 to 15, then decrease at day 22 (FLD group) and iii) stagnation of low levels all along (<1000 pg/mL from days 1 to 22, FLL group). The 16 evaluable ALL patients were classified as FLI (n=2), FLD (n=7) and FLL (n=7). All reached a cytologic complete remission after induction and only 2 relapses have been documented so far in this group. No impact of sFLc kinetic profile was seen in this context. Conversely, a significant impact of sFLc during induction (but not during consolidation) was observed in AML patients. The median age in this group was 59 years old (range: 29-71, <60 years n=33). The median follow-up for alive patients was 541 days (range: 154-787). sFLc levels were assayed in 244 samples. Twenty-six patients were classified as FLI (42%), 22 as FLD (35%) and 14 as FLL (23%). Median sFLc at days 1, 8, 15, 22 were as follows for the three groups: FLI: 2, 724, 3673, 5753 pg/mL; FLD: 6, 1229, 6019, 684 pg/mL; and FLL: 0, 60, 124, 81 pg/mL. There was no significant difference between the 3 groups regarding age, ELN 2010 risk-stratification (ELNrs), OMS classification, WBC and bone marrow blasts percentages at diagnosis. When comparing the 3 sFLc groups, almost all refractory patients (n=6) were found in the FLL group (n=5, FLD n=1, FLI n=0, p=0.0007). Three cytologic relapses occurred in the FLI group, 7 in the FLD group (cytologic n=4, molecular n=2, immunophenotypic n=1) and 7 in the FLL group (cytologic n=4, molecular n=2, immunophenotypic n=1). There were more relapses in the FLL group (n=7/9 [78%] vs FLD n=7/21 [33%] vs FLI n=3/26 [11.5%], p=0.0009). In univariate analysis, 2-year EFS and OS were significantly better for the FLI group (79.1+-8 vs FLD 54.9%+-11 vs FLL 11.4%+-10,p<0.001; and 80.4%+-8 vs FLD 58.6%+-11 vs FLL 18.6%+-10, p=0.09,respectively). There was a trend for the association of 2-year EFS (but not OS) with ELNrs (favorable:70.9%+-11, vs Int-1+Int-2:57.1%+-10 vs adverse 33%+-13,p=0.06). Stratification of the patients according to the median sFLc level at day +15 (2952pg/mL) also showed significantly different 2 year EFS at 38.2%+-9 for low levels vs 71.8%+-8 for high levels (p=0.02). The same was true for day +22 median sFLc level (1390pg/mL) at 38.9%+-9 vs 73.6%+-8 (p=0.02). Age had no impact on EFS nor OS. In multivariate analysis considering age, ELNrs, sFLc at days 15 and 22 levels, and sFLc kinetic profile during induction, the latter remained the most powerful factor independently associated with EFS (HR: 3.62; 95%CI: 1,65-7,94, p=0,001; ELNrs: HR: 1.74; 95%CI: 0,98-3.10, p=0.05; sFLc at day+15 p=0,37; sFLc at day+22, p=0.24, age p=NS). sFLc kinetic profile was the sole factor that was also independently associated with OS (HR: 2.60; 95%CI: 1.12-6,07, p=0.02). In conclusion, sFLc kinetic profile during induction appears to be a new powerful early prognostic parameter in AML patients. These results need to be validated on a larger cohort of patients and the mechanism by which induction sFLc levels may impact AML outcome remains to be elucidated. Disclosures Gastinne: Millennium/Takeda: Honoraria. Moreau:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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Pang, Liyan, Hai-Hui Xue, Gabor Szalai, Xun Wang, Yuhuan Wang, Dennis K. Watson, Warren J. Leonard, Gerd A. Blobel, and Mortimer Poncz. "Maturation stage–specific regulation of megakaryopoiesis by pointed-domain Ets proteins." Blood 108, no. 7 (October 1, 2006): 2198–206. http://dx.doi.org/10.1182/blood-2006-04-019760.
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Abstract Numerous megakaryocyte-specific genes contain signature Ets-binding sites in their regulatory regions. Fli-1 (friend leukemia integration 1), an Ets transcription factor, is required for the normal maturation of megakaryocytes and controls the expression of multiple megakaryocyte-specific genes. However, in Fli-1–/– mice, early megakaryopoiesis persists, and the expression of the early megakaryocyte-specific genes, αIIb and cMpl, is maintained, consistent with functional compensation by a related Ets factor(s). Here we identify the Ets protein GABPα (GA-binding protein α) as a regulator of early megakaryocyte-specific genes. Notably, GABPα preferentially occupies Ets elements of early megakaryocyte-specific genes in vitro and in vivo, whereas Fli-1 binds both early and late megakaryocyte-specific genes. Moreover, the ratio of GABPα/Fli-1 expression declines throughout megakaryocyte maturation. Consistent with this expression pattern, primary fetal liver–derived megakaryocytes from Fli-1–deficient murine embryos exhibit reduced expression of genes associated with late stages of maturation (glycoprotein [GP] Ibα, GPIX, and platelet factor 4 [PF4]), whereas GABPα-deficient megakaryocytes were mostly impaired in the expression of early megakaryocyte-specific genes (αIIb and cMpl). Finally, mechanistic experiments revealed that GABPα, like Fli-1, can impart transcriptional synergy between the hematopoietic transcription factor GATA-1 and its cofactor FOG-1 (friend of GATA-1). In concert, these data reveal disparate, but overlapping, functions of Ets transcription factors at distinct stages of megakaryocyte maturation.
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Jackers, Pascale, Gabor Szalai, Omar Moussa, and Dennis K. Watson. "Ets-dependent Regulation of Target Gene Expression during Megakaryopoiesis." Journal of Biological Chemistry 279, no. 50 (October 5, 2004): 52183–90. http://dx.doi.org/10.1074/jbc.m407489200.
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Megakaryopoiesis is the process by which hematopoietic stem cells in the bone marrow differentiate into mature megakaryocytes. The expression of megakaryocytic genes during megakaryopoiesis is controlled by specific transcription factors. Fli-1 and GATA-1 transcription factors are required for development of megakaryocytes and promoter analysis has definedin vitrofunctional binding sites for these factors in several megakaryocytic genes, includingGPIIb,GPIX, andC-MPL. Herein, we utilize chromatin immunoprecipitation to examine the presence of Ets-1, Fli-1, and GATA-1 on these promotersin vivo. Fli-1 and Ets-1 occupy the promoters ofGPIIb,GPIX, andC-MPLgenes in both Meg-01 and CMK11-5 cells. WhereasGPIIbis expressed in both Meg-01 and CMK11-5 cells,GPIXandC-MPLare only expressed in the more differentiated CMK11–5 cells. Thus,in vivooccupancy by an Ets factor is not sufficient to promote transcription of some megakaryocytic genes. GATA-1 and Fli-1 are both expressed in CMK11-5 cells and co-occupy theGPIXandC-MPLpromoters. Transcription of all three megakaryocytic genes is correlated with the presence of acetylated histone H3 and phosphorylated RNA polymerase II on their promoters. We also show that exogenous expression of GATA-1 in Meg-01 cells leads to the expression of endogenous c-mpl and gpIX mRNA. WhereasGPIIb,GPIX, andC-MPLare direct target genes for Fli-1, both Fli-1 and GATA-1 are required for formation of an active transcriptional complex on theC-MPLandGPIXpromotersin vivo. In contrast,GPIIbexpression appears to be independent of GATA-1 in Meg-01 cells.
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Tiemann, Katharina, Markus Kosmahl, Julia Ohlendorf, Matthias Krams, and Günter Klöppel. "Solid pseudopapillary neoplasms of the pancreas are associated with FLI-1 expression, but not with EWS/FLI-1 translocation." Modern Pathology 19, no. 11 (August 25, 2006): 1409–13. http://dx.doi.org/10.1038/modpathol.3800664.
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