Synergistic Activation of MAP Kinase (ERK1/2) by Erythropoietin and Stem Cell Factor Is Essential for Expanded Erythropoiesis

Sui, Xingwei; Krantz, Sanford B.; You, Min; Zhao, Zhizhuang Joe

doi:10.1182/blood.v92.4.1142

Cited by 122 publications

(57 citation statements)

References 43 publications

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“…In Epo-dependent HCD-57 cells that do not exhibit synergistic proliferation in response to Scf, activation of KIT by Scf was reported to mediate the tyrosine phosphorylation of EpoR (Wu et al, 1995b;Jacobs-Helber et al, 1997;Kapur et al, 1998). Phosphorylation of EpoR in response to Scf treatment was also reported in primary erythroid progenitors (Sui et al, 1998). In another study, Epo was reported to induce the tyrosine phosphorylation of KIT in UT7/Epo erythroleukaemia cells (Broudy et al, 1998).…”

Section: Discussionmentioning

confidence: 98%

Co‐operative signalling mechanisms required for erythroid precursor expansion in response to erythropoietin and stem cell factor

Arcasoy

Jiang

2005

Br J Haematol

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Summary The regeneration of circulating red blood cells in response to anaemia associated with blood loss or haemolysis involves an increased rate of erythropoiesis and expansion of proerythroblasts, the bone marrow precursor cells that terminally differentiate into mature erythrocytes. This study investigated the mechanisms by which erythropoietin (Epo) and stem cell factor (Scf) modulate the expansion of proerythroblasts. Homogenous populations of primary human proerythroblasts were generated in liquid cultures of CD34+ cells. In serum‐free cultures, proerythroblasts failed to survive in the presence of Epo or Scf alone, but exhibited synergistic proliferation in response to combined Epo and Scf treatment, exhibiting one‐log expansion in 5 d. Intracellular signal transduction in response to Epo and Scf revealed that tyrosine phosphorylation of signal transducers and activators of transcription (Stat) 5, a downstream target for the non‐receptor tyrosine kinase, Janus kinase 2 (Jak2), was mediated by Epo but not Scf. The mitogen‐activated protein kinases (MAPKs) extracellular regulated kinase (Erk) 1–2 were phosphorylated in response to either Epo or Scf. Phosphorylation of Akt, a signalling molecule downstream of phosphatidylinositol 3‐kinase (PI3K), was observed following Scf but not Epo treatment. To determine the contribution of specific signalling pathways to synergistic expansion of proerythroblasts in response to co‐operative effects of Epo and Scf, cells were treated with kinase inhibitors targeting Jak2, PI3K and MAPK kinase. There was a significant, dose‐dependent inhibition of proerythroblast expansion in response to all three kinase inhibitors. In conclusion, Epo‐ and Scf‐mediated co‐operative, synergistic expansion of primary erythroid precursors requires selective activation of multiple signalling pathways, including the Jak‐Stat, PI3K and MAPK pathways.

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Section: Discussionmentioning

confidence: 98%

Co‐operative signalling mechanisms required for erythroid precursor expansion in response to erythropoietin and stem cell factor

Arcasoy

Jiang

2005

Br J Haematol

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“…( Woessmann et al, 2004;Moosavi et al, 2007) Inhibition of induced mouse erythroleukaemia (MEL) cells with ERK and p38 pathway inhibitors resulted in an increase in intracellular haem and a decrease in haemoglobin levels. (Mardini et al, 2010) A role for MAPK in erythroid precursors has previously been demonstrated through inhibition of MAPK phosphorylation, which resulted in decreased erythroid colony formation (Sui et al, 1998) and reduced Pro-E expansion. (Arcasoy & Jiang, 2005) Moreover, in-vitro Pro-E cells from b-thalassaemia/Hb E have been shown to have increased phosphorylation of MAPK.…”

Section: Discussionmentioning

confidence: 99%

Differential gene expression analysis in early and late erythroid progenitor cells in β‐thalassaemia

et al. 2015

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Summaryb-thalassaemia is a disorder of globin gene synthesis resulting in reduced or absent production of the b-globin chain in red blood cells. In this study, haematopoietic stem cells were isolated from the peripheral blood of six transfusion dependent b-thalassaemia patients and six healthy controls. Following 7 and 14 d in culture, early-and late-erythroblasts were isolated and purified. No morphological difference in maturation was observed following 7 d in culture, while a delayed maturation was observed in the patient group after 14 d. Following RNA isolation and linear amplification, gene expression analyses were performed using microarray technology. The generated data were analysed by two methods: the BRB-ArrayTools platform and the Bioconductor platform using bead level data. Following 7 d culture, there was no difference in gene expression between the control and patient groups. Following 14 d culture, 384 differentially expressed genes were identified by either analysis. A subset of 90 genes was selected and the results were confirmed by Quantitative-Real-Time-polymerase chain reaction. Pathways shown to be significantly altered in the patient group include apoptosis, MAPKinase and the nuclear factor-jB pathway.

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“…A central role for ERKs in erythroid expansion has previously been demonstrated. Inhibition of ERKs phosphorylation with the MEK inhibitor PD98059 in normal primary erythroid cells resulted in a dose-dependent inhibition of erythroid colony formation (Sui et al, 1998) as well as a reduction of proerythroblast expansion (Arcasoy & Jiang, 2005). Additionally, expression of a constitutively active Ras, Raf or MEKs in primary erythroid cells not only constitutively activated ERKs phosphorylation, but also highly enhanced erythroid expansion in an EPO-independent manner (Zhang & Lodish, 2004).…”

Section: Discussionmentioning

confidence: 99%

Increased erythropoiesis of β‐thalassaemia/Hb E proerythroblasts is mediated by high basal levels of ERK1/2 activation

Wannatung¹,

Lithanatudom²,

Leecharoenkiat³

et al. 2009

Br J Haematol

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Increased erythropoiesis of b-thalassaemia/Hb E proerythroblasts is mediated by high basal levels of ERK1/2 activationThe thalassaemias are a group of disorders characterized by the under production of globin chains as a consequence of a wide range of underlying genetic abnormalities (Weatherall & Clegg, 2001). The a and b chains of haemoglobin A are the most commonly affected genes and both a-and b-thalassaemias represent a worldwide clinical problem (Weatherall & Clegg, 2001). The underproduction of one chain leads to a resultant excess of the other chain in the red cell that is toxic to the cell and leads to a reduced red cell life span, increased haemolysis and ineffective erythropoiesis, which is believed to arise through accelerated cell death by apoptosis of the immature erythroid cell (Yuan et al, 1993), either as a direct or indirect consequence of the unpaired globin chain deposition within the cell (Mathias et al, 2000). In b-thalassaemia apoptosis is believed to occur primarily at the polychromatophilic normoblast stage (Mathias et al, 2000). The combination of ineffective erythropoiesis, increased haemolysis and reduced life span of the mature red cell lead to the anaemic condition, which stimulates the production of erythropoietin (EPO) leading to erythroid hyperplasia in the bone marrow (Chen et al, 1992;Centis et al, 2000;Mathias et al, 2000;Pootrakul et al, 2000;Kittikalayawong et al, 2005;Mai et al, 2007) and markedly increased levels of circulating EPO have been documented in thalassaemic patients (Nisli et al, 1997;Chaisiripoomkere et al, 1999;Paritpokee et al, 2002). However, despite the increase in erythroid precursors, the overall response to the anaemia is limited due to the ineffective erythropoiesis leading to the accelerated death of immature erythroid cells. In severe cases of Summary b-thalassaemia is one of the most common inherited anaemias, arising from a partial or complete loss of b-globin chain synthesis. In severe cases, marked bone marrow erythroid hyperplasia, believed to result from erythropoietin (EPO)-mediated feedback from the anaemic condition is common, however, as yet, no study has investigated EPO-mediated signal transduction in thalassaemic erythroid cells. Using proerythroblasts generated from peripheral blood circulating CD34 + haematopoietic progenitor cells, the activation of the mitogen-activated protein kinase/extracellular signalregulated kinases (MAPK/ERKs) pathway was examined under conditions of steady state growth, cytokine deprivation and post-EPO stimulation. Levels of cellular cyclic adenosine monophosphate (cAMP) and Ca 2+ were determined as was the degree of erythroid expansion. A significantly higher basal level of phosphorylation of ERK1/2 was observed in b-thalassaemia/Hb E proerythroblasts as compared to normal controls, which was coupled with significantly higher levels of both cAMP and Ca 2+ . Modulation of either cAMP or Ca 2+ or direct inhibition of MAPK/ERK kinase (MEK) reduced basal levels of ERK1/2 phosphorylation, as well as significantly...

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Synergistic Activation of MAP Kinase (ERK1/2) by Erythropoietin and Stem Cell Factor Is Essential for Expanded Erythropoiesis

Cited by 122 publications

References 43 publications

Co‐operative signalling mechanisms required for erythroid precursor expansion in response to erythropoietin and stem cell factor

Co‐operative signalling mechanisms required for erythroid precursor expansion in response to erythropoietin and stem cell factor

Differential gene expression analysis in early and late erythroid progenitor cells in β‐thalassaemia

Increased erythropoiesis of β‐thalassaemia/Hb E proerythroblasts is mediated by high basal levels of ERK1/2 activation

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