Erythropoiesis-Stimulating Agents

Elliott, Steve

doi:10.1007/978-1-4419-7073-2_4

Cited by 11 publications

(8 citation statements)

References 133 publications

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“…Therefore, we have expected that the rescued mice would develop Epo-deficiency anaemia in adults. Expression profiles of the 3.3-Epo3 0 transgene appeared to be affected by The rHuEPO has been used widely as a powerful drug for anaemic patients [20][21][22] , but its downstream target genes are largely unknown. In this regard, previous studies mainly used primary culture systems for global gene expression analyses in which the erythroid precursors were stimulated with Epo 34,35 .…”

Section: Discussionmentioning

confidence: 99%

“…Recombinant Epo has been widely used to treat renal anaemia for more than 20 years, and next-generation erythropoiesis-stimulating agents (ESAs) have been developed 21,22 . As proper experimental animal systems of renal anaemia are still lacking, molecular effects and downstream target genes of recombinant Epo or ESAs in adult erythropoiesis have not been fully understood.…”

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confidence: 99%

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A mouse model of adult-onset anaemia due to erythropoietin deficiency

et al. 2013

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Erythropoietin regulates erythropoiesis in a hypoxia-inducible manner. Here we generate inherited super-anaemic mice (ISAM) as a mouse model of adult-onset anaemia caused by erythropoietin deficiency. ISAM express erythropoietin in the liver but lack erythropoietin production in the kidney. Around weaning age, when the major erythropoietin-producing organ switches from the liver to the kidney, ISAM develop anaemia due to erythropoietin deficiency, which is curable by administration of recombinant erythropoietin. In ISAM severe chronic anaemia enhances transgenic green fluorescent protein and Cre expression driven by the complete erythropoietin-gene regulatory regions, which facilitates efficient labelling of renal erythropoietin-producing cells. We show that the majority of cortical and outer medullary fibroblasts have the innate potential to produce erythropoietin, and also reveal a new set of erythropoietin target genes. ISAM are a useful tool for the evaluation of erythropoiesis-stimulating agents and to trace the dynamics of erythropoietin-producing cells.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

A mouse model of adult-onset anaemia due to erythropoietin deficiency

et al. 2013

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“…15 EPO is currently used in the treatment of low-risk MDS patients, mainly with the aim of correcting anemia. 16 However, little is known about the exact molecular mechanisms underlying the effect of EPO in low-risk MDS cells and the reasons why some patients do not respond to this treatment, even though some studies recently investigated whether EPO responder and nonresponder patients have different gene expression profiles. 17 Moreover, EPO is also able to compensate and counteract the ineffective erythropoiesis of MDS patients, therefore regulating cell metabolism, 18,19 via the activation of the EPO receptor, which is linked to the activation of both Akt and PI-PLCgamma1.…”

Section: Introductionmentioning

confidence: 99%

Activation of nuclear inositide signalling pathways during erythropoietin therapy in low-risk MDS patients

et al. 2012

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Inositide signaling pathways can have a role in the Myelodysplastic Syndromes (MDS) progression to acute myeloid leukemia. Erythropoietin (EPO) is currently used in low-risk MDS, where it successfully corrects anemia in 50-70% of patients. However, some MDS patients are refractory to this treatment and little is known about the exact molecular mechanisms underlying the effect of EPO in these subjects. Here, we investigated the role of inositide pathways in low-risk MDS treated with EPO, mainly focusing on the Akt/PI-PLC (Phosphoinositide-Phospholipase C) gamma1 axis, which is activated by the EPO receptor, and PI-PLCbeta1/Cyclin D3 signaling, as Cyclin D3 is associated with hematopoietic proliferation and differentiation. Interestingly, EPO responder patients showed a specific activation of both the Akt/PI-PLCgamma1 pathway and beta-Globin gene expression, while nonresponders displayed an increase in PI-PLCbeta1 signaling. Moreover, in normal CD34+ cells induced to erythroid differentiation, PI-PLCbeta1 overexpression abrogated both EPO-induced Akt phosphorylation and beta-Globin expression. Overall, these findings suggest that PI-PLCbeta1 can act as a negative regulator of erythroid differentiation and confirm the involvement of Akt/PI-PLCgamma1 pathway in EPO signaling, therefore contributing to the comprehension of the effect of EPO in low-risk MDS and possibly paving the way to the identification of MDS patients at higher risk of refractoriness to EPO treatment.

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“…2 E and F). Cultures were performed in the presence of erythropoietin [EPO, a cytokine that is required for proliferation of erythrocyte precursors (22)] to determine if MK1 also impacts erythropoiesis (Fig. S2).…”

Section: Resultsmentioning

confidence: 99%

An image-based screen identifies a small molecule regulator of megakaryopoiesis

Boitano

Lichtervelde

Snead

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Molecules that control the lineage commitment of hematopoietic stem cells (HSCs) may allow the expansion of enriched progenitor populations for both research and therapeutic uses. In an effort to better understand and control the differentiation of HSCs to megakaryocytes, we carried out an image-based screen of a library of 50,000 heterocycles using primary human CD34 + cells. A class of naphthyridinone derivatives was identified that induces the differentiation of common myeloid progenitors (CMP) to megakaryocytes. Kinase profiling and subsequent functional assays revealed that these compounds act through inhibition of platelet-derived growth factor receptor (PDGFR) signaling in CMPs. Such molecules may ultimately have clinical utility in the treatment of thrombocytopenia.

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Erythropoiesis-Stimulating Agents

Cited by 11 publications

References 133 publications

A mouse model of adult-onset anaemia due to erythropoietin deficiency

A mouse model of adult-onset anaemia due to erythropoietin deficiency

Activation of nuclear inositide signalling pathways during erythropoietin therapy in low-risk MDS patients

An image-based screen identifies a small molecule regulator of megakaryopoiesis

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