Aberrant alternative splicing of interferon regulatory factor-1 (IRF-1) in myelodysplastic hematopoietic progenitor cells

Maratheftis, Christos I.; Bolaraki, Pelagia E.; Giannouli, Stavroula; Kapsogeorgou, Efstathia K.; Moutsopoulos, Haralampos Μ.; Voulgarelis, Michael

doi:10.1016/j.leukres.2005.12.021

Cited by 15 publications

(8 citation statements)

References 25 publications

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“…The slope of the standard curve was converted to the amplification efficiency E by the following algorithm: E ¼ 10-1/ slope. The absence of nonspecific PCR products was also confirmed by melting curve analysis and gel electrophoresis [16].…”

Section: Quantitative Real-time Pcrmentioning

confidence: 86%

GATA‐1 transcription factor is up‐regulated in bone marrow hematopoietic progenitor CD34⁺ and erythroid CD71⁺ cells in myelodysplastic syndromes

2007

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GATA-1 is a transcription factor governing the production of erythroid and megakaryocytic cells. Unobstructed GATA-1 expression in early progenitor cells commits them to the myeloid lineage, channeling its differentiation towards erythrocytes and megakaryocytes. Myelodysplastic Syndromes (MDS) are clonal disorders of the hematopoietic stem cell frequently presenting dysplasia in erythroid and/or megakaryocytic lineage. We reasoned that measurement of GATA-1 expression levels in hematopoietic progenitor CD34 + and the committed erythroid CD71 + cells, from various MDS subcategories, could demonstrate GATA-1 involvement in the pathogenesis of the syndrome. In this study, MDS patients displayed significantly elevated GATA-1 mRNA expression, in bone marrow mononuclear cells (BMMCs), progenitor CD34 + and erythroid CD71+ cells in contrast to the control population (P < < 0.001). Additionally, GATA-1 mRNA expression in MDS CD71+ cells was positively correlated with their apoptotic levels (r = 0.58, P = 0.03). Furthermore, GATA-1 expression levels were found to correlate with the disease progression. MDS patients in high/INT-2 IPSS risk group expressed significantly higher GATA-1 mRNA levels, in both CD34 + and CD71 + cells, as opposed to low/INT-1 patients (P < 0.001). Moreover, the former displayed increased apoptosis in the CD71 + cells and significantly reduced neutrophil and platelet numbers and hemoglobin levels compared with the latter. We conclude that MDS patients display an increase of GATA-1 mRNA expression in BM cells, with high/INT-2 patients showing significantly higher levels. The higher level of GATA-1 mRNA in erythroid cells was positively correlated with their degree of apoptosis. These findings suggest that the up-regulation of GATA-1 may be responsible for the peripheral cytopenias in MDS. Am. J. Hematol. 82:887-892, 2007.

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Section: Quantitative Real-time Pcrmentioning

confidence: 86%

GATA‐1 transcription factor is up‐regulated in bone marrow hematopoietic progenitor CD34⁺ and erythroid CD71⁺ cells in myelodysplastic syndromes

2007

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“…It is known that MDS cells carry a number of genetic alternations that may affect the function of transcription factors (e.g., interferon regulatory factor-1 exon skipping; ref. 21 + cell apoptosis. Given the TNF elevated levels in MDS, the aptitude of TNF to induce TLR-4 expression, and the implication of TLR-4 in apoptosis, we suggest that increased TLR-4 expression may participate in MDS extensive apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…We designed oligonucleotide primers for each mRNA, consistent with the published sequences ( Table 2). Absolute quantification with the use of SYBR Green I dye and standard curves was applied as previously described (21).…”

Section: Methodsmentioning

confidence: 99%

Toll-like Receptor-4 Is Up-Regulated in Hematopoietic Progenitor Cells and Contributes to Increased Apoptosis in Myelodysplastic Syndromes

Maratheftis

Andreakos

Moutsopoulos

et al. 2007

Clinical Cancer Research

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Purpose: To investigate the function and expression of Toll-like receptors (TLR) in bone marrow cells of myelodysplastic syndrome (MDS) patients and to examine their involvement in the apoptotic phenomenon characterizing MDS hematopoiesis. Experimental Design: TLR mRNA and protein expression was investigated in bone marrow cell populations of MDS patients and controls. TLR-4 ability to recognize lipopolysaccharide and up-regulate self mRNA and protein expression was examined. Tumor necrosis factor involvement in the constitutive and lipopolysaccharide (LPS)-induced TLR expression was also evaluated. Possible correlation between TLR-4 overexpression and apoptosis was investigated by simultaneous staining with Annexin V and TLR-4. Results: TLR-2 and TLR-4 are expressed in almost all bone marrow cell lineages including megakaryocytes, erythroid cells, myeloid precursors, monocytes, and B lymphocytes and are up-regulated in MDS patients compared with controls. In hematopoietic CD34+ cells, TLR-4 is also expressed and significantly up-regulated at both the mRNA and protein levels. Treatment with an anti–tumor necrosis factor antibody reduces both constitutive and LPS-induced TLR-4 levels. Increased TLR-4 expression correlates with increased apoptosis as TLR-4 is almost exclusively found in apoptotic bone marrow mononuclear and CD34+ cells. The addition of the TLR-4 ligand LPS further enhances the apoptosis of these cells. Conclusions: TLR-4 and other TLRs are significantly up-regulated in MDS patients whereas TLR-4 is involved in promoting apoptosis, possibly contributing to MDS cytopenia.

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“…RPS19 deficiency also activates p53 and, like RPS14 deficiency, is associated with dyserythropoiesis. 105 Likewise, although lack of the IRF-1 gene expression has been observed in 100% of MDS patients assessed in one study, 106,107 IRF-1-/-mice show no sign of MDS development despite impaired granulocytic differentiation and decreased expression of C/EBPa and C/EBPe in CD11b + cells. 108 This tends to suggest that these abnormalities are not sufficient by themselves to confer disease.…”

Section: Tumor Suppressorsmentioning

confidence: 99%

Engineering mouse models with myelodysplastic syndrome human candidate genes; how relevant are they?

2012

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Myelodysplastic syndromes represent particularly challenging hematologic malignancies that arise from a large spectrum of genetic events resulting in a disease characterized by a range of different presentations and outcomes. Despite efforts to classify and identify the key genetic events, little improvement has been made in therapies that will increase patient survival. Animal models represent powerful tools to model and study human diseases and are useful pre-clinical platforms. In addition to enforced expression of candidate oncogenes, gene inactivation has allowed the consequences of the genetic effects of human myelodysplastic syndrome to be studied in mice. This review aims to examine the animal models expressing myelodysplastic syndrome-associated genes that are currently available and to highlight the most appropriate model to phenocopy myelodysplastic syndrome disease and its risk of transformation to acute myelogenous leukemia. ©2013 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol.2012.069385 ABSTRACTMouse models myelodysplastic syndrome human candidate genes haematologica | 2013; 98 (1) 11 Figure 1. Mouse models to study malignant hematologic disease. Several strategies can be employed to create mouse models of disease. Candidate genes can be introduced into the germline under the control of appropriate promoters to drive expression in certain cell compartments. Knock-out strategies create gene deficient mice, whilst knock-in strategies use the endogenous promoters; but again these tend to be conditional systems requiring specific promoters to determine in which cell the genes are introduced. Transduction of bone marrow and reinfusion is a powerful tool. Xenograft models are theoretically the best if the techniques involved can be improved.

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Aberrant alternative splicing of interferon regulatory factor-1 (IRF-1) in myelodysplastic hematopoietic progenitor cells

Cited by 15 publications

References 25 publications

GATA‐1 transcription factor is up‐regulated in bone marrow hematopoietic progenitor CD34⁺ and erythroid CD71⁺ cells in myelodysplastic syndromes

GATA‐1 transcription factor is up‐regulated in bone marrow hematopoietic progenitor CD34⁺ and erythroid CD71⁺ cells in myelodysplastic syndromes

Toll-like Receptor-4 Is Up-Regulated in Hematopoietic Progenitor Cells and Contributes to Increased Apoptosis in Myelodysplastic Syndromes

Engineering mouse models with myelodysplastic syndrome human candidate genes; how relevant are they?

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Aberrant alternative splicing of interferon regulatory factor-1 (IRF-1) in myelodysplastic hematopoietic progenitor cells

Cited by 15 publications

References 25 publications

GATA‐1 transcription factor is up‐regulated in bone marrow hematopoietic progenitor CD34+ and erythroid CD71+ cells in myelodysplastic syndromes

GATA‐1 transcription factor is up‐regulated in bone marrow hematopoietic progenitor CD34+ and erythroid CD71+ cells in myelodysplastic syndromes

Toll-like Receptor-4 Is Up-Regulated in Hematopoietic Progenitor Cells and Contributes to Increased Apoptosis in Myelodysplastic Syndromes

Engineering mouse models with myelodysplastic syndrome human candidate genes; how relevant are they?

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Product

Resources

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GATA‐1 transcription factor is up‐regulated in bone marrow hematopoietic progenitor CD34⁺ and erythroid CD71⁺ cells in myelodysplastic syndromes

GATA‐1 transcription factor is up‐regulated in bone marrow hematopoietic progenitor CD34⁺ and erythroid CD71⁺ cells in myelodysplastic syndromes