RHEX, a novel regulator of human erythroid progenitor cell expansion and erythroblast development

Verma, Rakesh; Su, Su; McCrann, Donald J.; Green, Jennifer M.; Leu, Karen; Young, Peter R.; Schatz, Peter J.; Silva, Jeffrey C.; Stokes, Matthew P.; Wojchowski, Don M.

doi:10.1084/jem.20130624

Cited by 33 publications

(34 citation statements)

References 27 publications

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“…In UT7epo cells, RHEX co-IP's with EPOR/JAK2 complexes, and its tyrosine phosphorylation is strongly induced by EPO. In primary EPCs, RHEX exhibits stage-specific expression, 47 and its knockdown attenuates extracellular signal-regulated kinase 1/2 (ERK1/2) activation as well as late-stage human erythroblast development. Interestingly, RHEX is not represented among rat, mouse, or lower vertebrates.…”

Section: 40mentioning

confidence: 99%

“…In addition, the novel hEPC protein RHEX associates with the hEPOR, enhances ERK1/2 activation, and supports erythroblast development. 47 Important downstream EPOR signal transducers are also being discovered ( Figure 1C). Within a central RAS/MEK module, these include MASL1, 63 Rasa3, 56 and neurofibrin, 57 that act to balance ERK1/2 signaling and EPC production.…”

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confidence: 99%

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Emerging EPO and EPO receptor regulators and signal transducers

Kuhrt

Wojchowski

2015

Blood

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129

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As essential mediators of red cell production, erythropoietin (EPO) and its cell surface receptor (EPO receptor [EPOR]) have been intensely studied. Early investigations defined basic mechanisms for hypoxia-inducible factor induction of EPO expression, and within erythroid progenitors EPOR engagement of canonical Janus kinase 2/signal transducer and activator of transcription 5 (JAK2/STAT5), rat sarcoma/mitogen-activated protein kinase/ extracellular signal-regulated kinase (RAS/ MEK/ERK), and phosphatidylinositol 3-kinase (PI3K) pathways. Contemporary genetic, bioinformatic, and proteomic approaches continue to uncover new clinically relevant modulators of EPO and EPOR expression, and EPO's biological effects. This Spotlight review highlights such factors and their emerging roles during erythropoiesis and anemia. (Blood. 2015;125(23):3536-3541)

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Section: 40mentioning

confidence: 99%

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confidence: 99%

Emerging EPO and EPO receptor regulators and signal transducers

Kuhrt

Wojchowski

2015

Blood

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146

129

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“…The biochemical basis for these differences is starting to emerge. In fact, the signaling cascade of the EPO receptor includes Ca 2+ mobilization and the regulator of human erythroid cell expansion (RHEX) factor in human but not in murine erythroid cells genome . The use of improved culture models of human erythropoiesis has been favored by the development of retroviral technologies, which allow altering gene expression or performing gene editing with low numbers of human stem cells.…”

Section: Rationale Supporting the Use Of Improved In Vitro Models To mentioning

confidence: 99%

Concise Review: Advanced Cell Culture Models for Diamond Blackfan Anemia and Other Erythroid Disorders

Migliaccio

Varricchio

2017

Stem Cells

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In vitro surrogate models of human erythropoiesis made many contributions to our understanding of the extrinsic and intrinsic regulation of this process in vivo and how they are altered in erythroid disorders. In the past, variability among the levels of hemoglobin F produced by adult erythroblasts generated in vitro by different laboratories identified stage of maturation, fetal bovine serum, and accessory cells as "confounding factors," that is, parameters intrinsically wired in the experimental approach that bias the results observed. The discovery of these factors facilitated the identification of drugs that accelerate terminal maturation or activate specific signaling pathways for the treatment of hemoglobinopathies. It also inspired studies to understand how erythropoiesis is regulated by macrophages present in the erythroid islands. Recent cell culture advances have greatly increased the number of human erythroid cells that can be generated in vitro and are used as experimental models to study diseases, such as Diamond Blackfan Anemia, which were previously poorly amenable to investigation. However, in addition to the confounding factors already identified, improvement in the culture models has introduced novel confounding factors, such as possible interactions between signaling from cKIT, the receptor for stem cell factor, and from the glucocorticoid receptor, the cell proliferation potential and the clinical state of the patients. This review will illustrate these new confounding factors and discuss their clinical translation potential to improve our understanding of Diamond Blackfan Anemia and other erythroid disorders. STEM CELLS 2018;36:172-179 SIGNIFICANCE STATEMENTBy contrast with theoretical science, experimental science tests models that by definition are imperfect because they contain "confounding factors." In the past, confounding factors identified in the in vitro models developed to study human erythropoiesis have greatly contributed to advance the field. Recent technological advances have greatly improved the power of analyses provided by in vitro models of human erythropoiesis. However, these improved models contain novel "confounding factors" that have yet to be fully discussed. This review will illustrate three novel confounding factors wired in advanced in vitro models of human erythropoiesis and discuss how their identification may drive additional studies to improve our understanding of the pathobiology of Diamond Blackfan Anemia and possibly other erythroid disorders.

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“…As examples, the induction of late-stage factors in murine EPCs is more accelerated; MAPK signaling modules are incongruous in their up- vs down-modulated components 142 ; and non-coding RNA populations are particularly disparate including several that promote the late-stage development of murine EPCs but are absent from H. sapiens 143 . Differences between mouse and human erythropoiesis also are illustrated (for example) by the lack of disease phenotypes in mice harboring a hematopoietic deficiency in SEC23B 144 (a condition genetically known to underlie congenital dyserythropoietic anemia type II), and by the discovery of C1ORF186/”RHEX” as a novel EPO/EPOR target and molecular adaptor which has evolved in H sapiens EPCs but not in mice, rats or lower vertebrates 145 .…”

Section: ] Model Systems For the Discovery And Validation Of New Drumentioning

confidence: 99%

“…For human EPCs, major advances have been made for two-phase serum-free ex vivo systems that employ dexamethasone to efficiently generate CFUe and (pro)erythroblasts 145 , and for three-phase systems that further support development to anucleated erythrocytes 142 . As primary sources, peripheral blood monocytes, mobilized CD34 pos progenitors, or cord blood progenitors can be used.…”

Section: ] Model Systems For the Discovery And Validation Of New Drumentioning

confidence: 99%

Targeting EPO and EPO receptor pathways in anemia and dysregulated erythropoiesis

Rainville

Jachimowicz

Wojchowski

2015

Expert Opinion on Therapeutic Targets

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Introduction Recombinant human erythropoietin (rhEPO) is a first-line therapeutic for the anemia of chronic kidney disease, cancer chemotherapy, AIDS (Zidovudine therapy) and lower-risk myelodysplastic syndrome. However, rhEPO frequently elevates hypertension, is costly and may affect cancer progression. Potential high merit therefore exists for defining new targets for anti-anemia agents within EPO, and EPO receptor (EPOR) regulatory circuits. Areas covered EPO production by renal interstitial fibroblasts is subject to modulation by several regulators of hypoxia-inducible factor 2a (HIF2a) including Iron Response Protein-1, prolyl hydroxylases and HIF2a acetylases, each with potential as anti-anemia drug targets. The cell surface receptor for EPO (EPOR) preassembles as a homodimer (together with JAK2), and novel agents that trigger EPOR complex activation also remain attractive to develop (activating antibodies, mimetics, small molecule agonists). Additionally, certain downstream transducers of EPOR/JAK2 signaling may be drugable including Erythroferrone (a hepcidin regulator), a cytoprotective Spi2a serpin, and select EPOR-associated protein tyrosine phosphatases. Expert Opinion While rhEPO (and biosimilars) presently are important mainstay erythropoiesis-stimulating agents, impetus exists for studies of novel ESAs that fortify HIF2a’s effects, act as EPOR agonists, and/or bolster select downstream EPOR pathways to erythroid cell formation. Such agents could lessen rhEPO dosing, side effects and/or costs.

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RHEX, a novel regulator of human erythroid progenitor cell expansion and erythroblast development

Abstract: RHEX is a novel target of the human erythropoietin receptor, and modulator of EPO-dependent red cell production.

Cited by 33 publications

References 27 publications

Emerging EPO and EPO receptor regulators and signal transducers

Emerging EPO and EPO receptor regulators and signal transducers

Concise Review: Advanced Cell Culture Models for Diamond Blackfan Anemia and Other Erythroid Disorders

Targeting EPO and EPO receptor pathways in anemia and dysregulated erythropoiesis

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