ETS-1 induces increased expression of erythroid markers in the pluripotent erythroleukemic cell lines K562 and HEL

Clausen, P Prætorious; Athanasiou, Meropi; Chen, None Zhi‐Duan; Dunn, KJ; Zhang, Q; Lautenberger, J. A.; Mavrothalassitis, George; Blair, D. G.

doi:10.1038/sj.leu.2400735

Cited by 27 publications

(27 citation statements)

References 19 publications

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“…28 Together with the data we have present here, our results suggest a model in which FLI-1 acts in a reciprocal fashion to promote megakaryocytic and inhibit erythroid differentiation. They indicate that ETS transcription factors can act coordinately and in opposition to one another, and suggest that the balance of these factors may play a crucial role in determining the fate of cells along the erythroid/megakaryocytic pathway.…”

Section: Discussionsupporting

confidence: 60%

“…Consistent with its ability to induce erythroid differentiation, 24,27 treatment with hemin increased the fraction of benzidine-positive cells, indicating increased hemoglobin levels ( Table 1). As previously reported, [28][29][30][31] hemoglobin levels in K562 cells were also responsive to hemin, but the endogenous level of FLI-1 in these cells was too low to determine if they were reduced in cells treated with these inducers (data not shown).…”

Section: Fli-1 Expression Is Down-regulated During Induction Of Erythsupporting

confidence: 46%

“…As shown in Table 3, FLI-1-expressing K562 populations show reduced levels of benzidine-positive cells in response to treatment with either erythroid inducer. HEL cells, which in our experiments are not responsive to Ara-C, 28 are also less responsive to hemin if they are infected with the FLI-1-expressing virus. Flow cytometry measurement of the erythroid marker CD71 level showed a 28% reduction (compared to vector-infected controls) in the response of K562 to Ara-C, while the response of HEL cells to this inducer was completely blocked (Table 3).…”

Section: Fli-1 Overexpression Inhibits the Response Of Both K562 And mentioning

confidence: 86%

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FLI-1 is a suppressor of erythroid differentiation in human hematopoietic cells

et al. 2000

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The FLI-1 oncogene, a member of the ETS family of transcription factors, is associated with both normal and abnormal hematopoietic cell growth and lineage-specific differentiation. We have previously shown that overexpression of FLI-1 in pluripotent human hematopoietic cells leads to the induction of a megakaryocytic phenotype. In this report we show that FLI-1 also acts as an inhibitor of erythroid differentiation. Following the induction of erythroid differentiation, pluripotent cells express reduced levels of FLI-1. In contrast, when FLI-1 is overexpressed in these cells, the levels of erythroid markers are reduced. The ability of FLI-1 overexpressing cells to respond to erythroid-specific inducers such as hemin and Ara-C is also inhibited, and the uninduced cells show a reduced level of the erythroid-associated GATA-1 transcription factor mRNA. Furthermore, expression of a GATA-1 promoter-driven reporter construct in K562 cells is inhibited by co-transfection with a construct expressing FLI-1. Our results support the hypothesis that FLI-1 can act both positively and negatively in the regulation of hematopoietic cell differentiation, and that inhibition of GATA-1 expression may contribute to FLI-1-mediated inhibition of erythroid differentiation. Leukemia (2000) 14, 439-445.

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Section: Discussionsupporting

confidence: 60%

Section: Fli-1 Expression Is Down-regulated During Induction Of Erythsupporting

confidence: 46%

Section: Fli-1 Overexpression Inhibits the Response Of Both K562 And mentioning

confidence: 86%

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FLI-1 is a suppressor of erythroid differentiation in human hematopoietic cells

et al. 2000

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“…9 Despite extensive studies on Ets-1, its role in myeloid hematopoietic cells is still largely unexplored. In erythropoiesis it is debated whether Ets-1 acts as a positive regulator 10,11 or as an inhibitor of erythroid differentiation. 12,13 In megakaryocytopoiesis Ets-1 is upregulated 14 and, Ets binding sites (EBS) have been identified in many megakaryocyte-specific gene promoters.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Ets-1 in human hematopoietic progenitor cells blocks erythroid and promotes megakaryocytic differentiation

et al. 2005

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Ets-1 is a widely expressed transcription factor implicated in development, tumorigenesis and hematopoiesis. We analyzed Ets-1 gene expression during human erythroid and megakaryocytic (MK) differentiation in unilineage cultures of CD34 þ progenitor cells. During erythroid maturation, Ets-1 is downmodulated and exported from the nucleus into the cytoplasm through an active mechanism mediated by a leucine-rich nuclear export signal. In contrast, during megakaryocytopoiesis Ets-1 increases and remains localized in the nucleus up to terminal maturation. Overexpression of Ets-1 in erythroid cells blocks maturation at the polychromatophilic stage, increases GATA-2 and decreases both GATA-1 and erythropoietin receptor expression. Conversely, Ets-1 overexpressing megakaryocytes are characterized by enhanced differentiation and maturation, coupled with upmodulation of GATA-2 and megakaryocyte-specific genes. We show that Ets-1 binds to and activates the GATA-2 promoter, in vitro and in vivo, indicating that one of the pathways through which Ets-1 blocks erythroid and promotes MK differentiation is via upmodulation of GATA-2 expression.

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“…In contrast to FLI1, however, ETS1 is dispensable for megakaryopoiesis in vivo because Ets-1 -/-mice exhibit normal MK differentiation while displaying other hematopoietic defects (15). Moreover, in vitro overexpression of ETS1 in human pluripotent hematopoietic cell lines favors the development of an erythroid phenotype (16), while that of FLI1 induces MK markers (17). Taken as a whole, these data suggest that FLI1 hemizygous deletion might be at least partly responsible for the platelet/MK defects observed in PTS patients.…”

Section: Introductionmentioning

confidence: 99%

FLI1 monoallelic expression combined with its hemizygous loss underlies Paris-Trousseau/Jacobsen thrombopenia

Raslová

Komura²,

Couedic³

et al. 2004

J. Clin. Invest.

146

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Paris-Trousseau syndrome (PTS; also known as Jacobsen syndrome) is characterized by several congenital anomalies including a dysmegakaryopoiesis with two morphologically distinct populations of megakaryocytes (MKs). PTS patients harbor deletions on the long arm of chromosome 11, including the FLI1 gene, which encodes a transcription factor essential for megakaryopoiesis. We show here that lentivirus-mediated overexpression of FLI1 in patient CD34 + cells restores the megakaryopoiesis in vitro, indicating that FLI1 hemizygous deletion contributes to the PTS hematopoietic defects. FISH analysis on pre-mRNA and single-cell RT-PCR revealed that FLI1 expression is mainly monoallelic in CD41 + CD42 -progenitors, while it is predominantly biallelic in the other stages of megakaryopoiesis. In PTS cells, the hemizygous deletion of FLI1 generates a subpopulation of CD41 + CD42 -cells completely lacking FLI1 transcription. We propose that the absence of FLI1 expression in these CD41 + CD42 -cells might prevent their differentiation, which could explain the segregation of the PTS MKs into two subpopulations: one normal and one composed of small immature MKs undergoing a massive lysis, presumably originating from either FLI1 + or FLI1 -CD41 + CD42 -cells, respectively. Thus, we point to the role of transient monoallelic expression of a gene essential for differentiation in the genesis of human haploinsufficiency-associated disease and suggest that such a mechanism may be involved in the pathogenesis of other congenital or acquired genetic diseases.

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ETS-1 induces increased expression of erythroid markers in the pluripotent erythroleukemic cell lines K562 and HEL

Cited by 27 publications

References 19 publications

FLI-1 is a suppressor of erythroid differentiation in human hematopoietic cells

FLI-1 is a suppressor of erythroid differentiation in human hematopoietic cells

Overexpression of Ets-1 in human hematopoietic progenitor cells blocks erythroid and promotes megakaryocytic differentiation

FLI1 monoallelic expression combined with its hemizygous loss underlies Paris-Trousseau/Jacobsen thrombopenia

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