EPO and EPO-Receptor System as Potential Actionable Mechanism for the Protection of Brain and Heart in Refractory Epilepsy and SUDEP

2020 ◽  
Vol 26 (12) ◽  
pp. 1356-1364 ◽  
Author(s):  
Jerónimo Auzmendi ◽  
María B. Puchulu ◽  
Julio C. G. Rodríguez ◽  
Ana M. Balaszczuk ◽  
Alberto Lazarowski ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Wide Spectrum ◽  
Cell Types ◽  
Heart Tissue ◽  
Erythropoietin Receptor ◽  
Protective Effects ◽  
Receptor System ◽  
Erythroid Progenitor ◽  
Neuronal Populations ◽  
Hypoxic Conditions

The most important activity of erythropoietin (EPO) is the regulation of erythrocyte production by activation of the erythropoietin receptor (EPO-R), which triggers the activation of anti-apoptotic and proliferative responses of erythroid progenitor cells. Additionally, to erythropoietic EPO activity, an antiapoptotic effect has been described in a wide spectrum of tissues. EPO low levels are found in the central nervous system (CNS), while EPO-R is expressed in most CNS cell types. In spite of EPO-R high levels expressed during the hypoxicischemic brain, insufficient production of endogenous cerebral EPO could be the cause of determined circuit alterations that lead to the loss of specific neuronal populations. In the heart, high EPO-R expression in cardiac progenitor cells appears to contribute to myocardial regeneration under EPO stimulation. Several lines of evidence have linked EPO to an antiapoptotic role in CNS and in heart tissue. In this review, an antiapoptotic role of EPO/EPO-R system in both brain and heart under hypoxic conditions, such as epilepsy and sudden death (SUDEP) has been resumed. Additionally, their protective effects could be a new field of research and a novel therapeutic strategy for the early treatment of these conditions and avoid SUDEP.

Abstract 018: Rat Ckit+ Cardiac Progenitor Cells Release Pro-survival Micrornas In Exosomes Following Hypoxic Stimulation.

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Warren D Gray ◽  
Nnenna Finn ◽  
Charles Searles ◽  
Michael E Davis
Keyword(s):  
Progenitor Cells ◽  
Cell Types ◽  
Cardiac Progenitor Cells ◽  
Protective Effects ◽  
Mrna Targets ◽  
Hypoxic Conditions ◽  
Infarcted Heart ◽  
Developed Nations ◽  
Future Work ◽  
Infarcted Region

Introduction: Cardiovascular disease is the leading cause of morbidity and mortality among developed nations, and acute myocardial infarction is the major subgroup. The need exists for cardiac therapeutic systems that mitigate tissue damage and induce regeneration within and around the infarcted region. Cardiac progenitor cells (CPCs) and other stem cell types have been attractive candidates for therapies. However, results suggest that regenerative or protective effects may occur through paracrine mechanisms. One such way may be through cell-cell transfer of microRNA (miR) via cell-secreted exosomes, which contain protein, mRNA, and miR. Cell-based therapies face substantial limitations, and therapies avoid these limitations and mimic paracrine efforts—such as delivery of harvested exosomes—have yet to be developed due in part to lack of characterization. Hypothesis: We hypothesized that in response to hypoxic conditions, CPCs secrete a pro-regenerative miRnome within exosomes. Methods: We used an Affymetrix MicroRNA GeneChip microarray to identify the miR populations that were present in CPC-conditioned media after hypoxic and normoxic treatments. Exosomes were isolated via ultracentrifugation (100,000xG) and validated by anti-CD9 immunohistochemistry and dynamic light scattering. We used RT-qPCR to quantify levels of miR upregulation in secreted exosomes. Results: We found seven miRs upregulated (1.3- to 7.9-fold) due to hypoxia stimulation. Within that miRnome, two miRs ([[Unable to Display Character: ‐]]20a, [[Unable to Display Character: ‐]]210) are known to exert cardioprotection in infarct models, providing evidence of a potential beneficial paracrine effect from CPCs. Four of the remaining miRs (-15b, -17, -103, -199a) have been shown to regulate angiogenesis, proliferation, apoptosis, and fibrosis in various cell and tissue types. One miR ([[Unable to Display Character: ‐]]292) has been largely unexplored, but predicted mRNA targets include CTGF, which is involved in cell adhesion and fibrosis. Conclusions: The strong evidence of anti-apoptotic and anti-fibrotic potential of this miRnome indicates that the cocktail may serve as a powerful modulator of cardiac remodeling. Future work will investigate applying miR-containing exosomes from hypoxia-stimulated CPCs as a therapy to rescue the infarcted heart.

scholarly journals A constitutively activated erythropoietin receptor stimulates proliferation and contributes to transformation of multipotent, committed nonerythroid and erythroid progenitor cells.

1994 ◽  
Vol 14 (4) ◽  
pp. 2266-2277 ◽  
Author(s):  
G D Longmore ◽  
P N Pharr ◽  
H F Lodish
Keyword(s):  
Cell Line ◽  
Progenitor Cells ◽  
Cell Lines ◽  
Leukemia Virus ◽  
Active Form ◽  
Erythropoietin Receptor ◽  
Mutant Form ◽  
Erythroid Progenitors ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells

If the env gene of spleen focus-forming virus (SFFV) is replaced by a cDNA encoding a constitutively active form of the erythropoietin receptor, EPO-R(R129C), the resultant recombinant virus, SFFVcEPO-R, induces transient thrombocytosis and erythrocytosis in infected mice. Clonogenic progenitor cell assays of cells from the bone marrow and spleens of these infected mice suggest that EPO-R(R129C) can stimulate proliferation of committed megakaryocytic and erythroid progenitors as well as nonerythroid multipotent progenitors. From the spleens of SFFVcEPO-R-infected mice, eight multiphenotypic immortal cell lines were isolated and characterized. These included primitive erythroid, lymphoid, and monocytic cells. Some expressed proteins characteristic of more than one lineage. All cell lines resulting from SFFVcEPO-R infection contained a mutant form of the p53 gene. However, in contrast to infection by SFFV, activation of PU.1 gene expression, by retroviral integration, was not observed. One cell line had integrated a provirus upstream of the fli-1 gene, in a location typically seen in erythroleukemic cells generated by Friend murine leukemia virus infection. This event led to increased expression of fli-1 in this cell line. Thus, infection by SFFVcEPO-R can induce proliferation and lead to transformation of nonerythroid as well as very immature erythroid progenitor cells. The sites of proviral integration in clonal cell lines are distinct from those in SFFV-derived lines.

A Minimal Cytoplasmic Subdomain of the Erythropoietin Receptor Mediates Erythroid and Megakaryocytic Cell Development

Blood ◽  
1999 ◽  
Vol 94 (10) ◽  
pp. 3381-3387 ◽  
Author(s):  
Chris P. Miller ◽  
Zi Y. Liu ◽  
Constance T. Noguchi ◽  
Don M. Wojchowski
Keyword(s):  
Progenitor Cells ◽  
Ex Vivo ◽  
Fetal Liver ◽  
Cell Development ◽  
Erythropoietin Receptor ◽  
Erythroid Progenitor ◽  
Epo Receptor ◽  
Receptor Complexes ◽  
Erythroid Progenitor Cells ◽  
Fetal Liver Cells

Signals provided by the erythropoietin (Epo) receptor are essential for the development of red blood cells, and at least 15 distinct signaling factors are now known to assemble within activated Epo receptor complexes. Despite this intriguing complexity, recent investigations in cell lines and retrovirally transduced murine fetal liver cells suggest that most of these factors and signals may be functionally nonessential. To test this hypothesis in erythroid progenitor cells derived from adult tissues, a truncated Epo receptor chimera (EE372) was expressed in transgenic mice using a GATA-1 gene-derived vector, and its capacity to support colony-forming unit-erythroid proliferation and development was analyzed. Expression at physiological levels was confirmed in erythroid progenitor cells expanded ex vivo, and this EE372 chimera was observed to support mitogenesis and red blood cell development at wild-type efficiencies both independently and in synergy with c-Kit. In addition, the activity of this minimal chimera in supporting megakaryocyte development was tested and, remarkably, was observed to approximate that of the endogenous receptor for thrombopoietin. Thus, the box 1 and 2 cytoplasmic subdomains of the Epo receptor, together with a tyrosine 343 site (each retained within EE372), appear to provide all of the signals necessary for the development of committed progenitor cells within both the erythroid and megakaryocytic lineages.

scholarly journals Antibody-Mediated Enhancement of Parvovirus B19 Uptake into Endothelial Cells Mediated by a Receptor for Complement Factor C1q

2014 ◽  
Vol 88 (14) ◽  
pp. 8102-8115 ◽  
Author(s):  
Kristina von Kietzell ◽  
Tanja Pozzuto ◽  
Regine Heilbronn ◽  
Tobias Grössl ◽  
Henry Fechner ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Progenitor Cells ◽  
Parvovirus B19 ◽  
Cell Types ◽  
Complement Factor ◽  
Human Parvovirus B19 ◽  
Erythroid Progenitor ◽  
Antibody Dependent Enhancement ◽  
Erythroid Progenitor Cells ◽  
Additional Cell

ABSTRACTDespite its strong host tropism for erythroid progenitor cells, human parvovirus B19 (B19V) can also infect a variety of additional cell types. Acute and chronic inflammatory cardiomyopathies have been associated with a high prevalence of B19V DNA in endothelial cells of the myocardium. To elucidate the mechanisms of B19V uptake into endothelium, we first analyzed the surface expression of the well-characterized primary B19V receptor P antigen and the putative coreceptors α5β1integrins and Ku80 antigen on primary and permanent endothelial cells. The receptor expression pattern and also the primary attachment levels were similar to those in the UT7/Epo-S1 cell line regarded as functional for B19V entry, but internalization of the virus was strongly reduced. As an alternative B19V uptake mechanism in endothelial cells, we demonstrated antibody-dependent enhancement (ADE), with up to a 4,000-fold increase in B19V uptake in the presence of B19V-specific human antibodies. ADE was mediated almost exclusively at the level of virus internalization, with efficient B19V translocation to the nucleus. In contrast to monocytes, where ADE of B19V has been described previously, enhancement does not rely on interaction of the virus-antibody complexes with Fc receptors (FcRs), but rather, involves an alternative mechanism mediated by the heat-sensitive complement factor C1q and its receptor, CD93. Our results suggest that ADE represents the predominant mechanism of endothelial B19V infection, and it is tempting to speculate that it may play a role in the pathogenicity of cardiac B19V infection.IMPORTANCEBoth efficient entry and productive infection of human parvovirus B19 (B19V) seem to be limited to erythroid progenitor cells. However,in vivo, the viral DNA can also be detected in additional cell types, such as endothelial cells of the myocardium, where its presence has been associated with acute and chronic inflammatory cardiomyopathies. In this study, we demonstrated that uptake of B19V into endothelial cells most probably does not rely on the classical receptor-mediated route via the primary B19V receptor P antigen and coreceptors, such as α5β1integrins, but rather on antibody-dependent mechanisms. Since the strong antibody-dependent enhancement (ADE) of B19V entry requires the CD93 surface protein, it very likely involves bridging of the B19V-antibody complexes to this receptor by the complement factor C1q, leading to enhanced endocytosis of the virus.

scholarly journals Erythropoietin in Brain Development and Beyond

2012 ◽  
Vol 2012 ◽  
pp. 1-15 ◽  
Author(s):  
Mawadda Alnaeeli ◽  
Li Wang ◽  
Barbora Piknova ◽  
Heather Rogers ◽  
Xiaoxia Li ◽  
...  
Keyword(s):  
Blood Cell ◽  
Red Blood Cell ◽  
Cell Types ◽  
Erythropoietin Receptor ◽  
Adult Brain ◽  
Receptor Expression ◽  
Neural Cells ◽  
Erythroid Progenitor ◽  
Cell Production ◽  
Oxygen Carrying Capacity

Erythropoietin is known as the requisite cytokine for red blood cell production. Its receptor, expressed at a high level on erythroid progenitor/precursor cells, is also found on endothelial, neural, and other cell types. Erythropoietin and erythropoietin receptor expression in the developing and adult brain suggest their possible involvement in neurodevelopment and neuroprotection. During ischemic stress, erythropoietin, which is hypoxia inducible, can contribute to brain homeostasis by increasing red blood cell production to increase the blood oxygen carrying capacity, stimulate nitric oxide production to modulate blood flow and contribute to the neurovascular response, or act directly on neural cells to provide neuroprotection as demonstrated in culture and animal models. Clinical studies of erythropoietin treatment in stroke and other diseases provide insight on safety and potential adverse effects and underscore the potential pleiotropic activity of erythropoietin. Herein, we summarize the roles of EPO and its receptor in the developing and adult brain during health and disease, providing first a brief overview of the well-established EPO biology and signaling, its hypoxic regulation, and role in erythropoiesis.

Evidence of synergistic/additive effects of sildenafil and erythropoietin in enhancing survival and migration of hypoxic endothelial cells

2013 ◽  
Vol 304 (4) ◽  
pp. L230-L239 ◽  
Author(s):  
Elena Gammella ◽  
Caroline Leuenberger ◽  
Max Gassmann ◽  
Louise Ostergaard
Keyword(s):  
Endothelial Cells ◽  
Combination Treatment ◽  
Synergistic Effects ◽  
Annexin V ◽  
Cell Types ◽  
Blue Staining ◽  
Protective Effects ◽  
Hypoxic Conditions ◽  
Phosphodiesterase Type 5 Inhibitor ◽  
And Migration

Endothelial cell dysfunction is a common event to several pathologies including pulmonary hypertension, which is often associated with hypoxia. As the endothelium plays an essential role in regulating the dynamic interaction between pulmonary vasodilatation and vasoconstriction, this cell type is fundamental in the development of vascular remodeling and increased vascular resistance. We investigated the protective effects of sildenafil, a phosphodiesterase type 5 inhibitor, given in combination with erythropoietin (Epo), as it has been demonstrated that both drugs have antiapoptotic effects on several cell types. Specifically, we examined the viability and angiogenic properties of rat pulmonary artery endothelial cells upon exposure to either 21% or 1% oxygen, in presence of sildenafil (1 and 100 nM) and Epo (5 and 20 U/ml) alone or in combination (1 nM and 20 U/ml). Cell proliferation and viability were analyzed by Trypan blue staining, MTT assay, and Annexin V/propidium iodide stainings. In all assays, the ability of the combination treatment in improving cell viability was superior to that of either drug alone. The angiogenic properties were studied using a migration and a 3D collagen assay, and the results revealed increases in the migration potential of endothelial cells as well as the ability to form tube-like structures in response to sildenafil and the combination treatment. We therefore conclude that both drugs exert protective effects on endothelial cells on hypoxia and that sildenafil enhances the migratory and angiogenic properties, especially in hypoxic conditions. Furthermore, we present evidence of possible additive or synergistic effects of both drugs.

Mechanism of erythropoietin action on the erythroid progenitor cells induced from murine erythroleukemia cells (TSA8)

Development ◽  
1989 ◽  
Vol 105 (1) ◽  
pp. 109-114 ◽  
Author(s):  
H. Fukumoto ◽  
Y. Matsui ◽  
M. Obinata
Keyword(s):  
Progenitor Cells ◽  
Phosphodiesterase Inhibitor ◽  
Second Messenger ◽  
Erythroid Differentiation ◽  
Camp Level ◽  
Erythropoietin Receptor ◽  
Erythroid Progenitor ◽  
Erythroleukemia Cells ◽  
Murine Erythroleukemia ◽  
Murine Erythroleukemia Cells

Erythropoietin is a well-known erythroid differentiation and growth factor, but the mechanism of its action is not well understood. In this work, we have examined its mechanism of action on the erythropoietin-responsive murine erythroleukemia cells (TSA8). TSA8 cells become responsive to erythropoietin after induction with DMSO. Stimulatory effects on erythropoietin response are observed with the addition of compounds affecting the cAMP level such as forskolin, phosphodiesterase inhibitor and cholera toxin only in the presence of erythropoietin. cAMP analogues themselves show no stimulatory effect on TSA8 cells, nor does erythropoietin increase cAMP level in the cells. Thus, it is suggested that cAMP does not act as a direct second messenger for signal transduction through erythropoietin receptors, but as a stimulator of the erythropoietin receptor pathway and/or as a second messenger in combination with the receptor pathway. The mechanism for acquisition of responsiveness to growth and differentiation factors of progenitor cells is discussed.

Gab1 Is Involved in Erythropoietin Receptor-Mediated Survival Signal through Activation of the Erk Pathway.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2207-2207
Author(s):  
Tetsuya Fukumoto ◽  
Yoshitsugu Kubota ◽  
Akira Kitanaka ◽  
Fusako Waki ◽  
Osamu Imataki ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Adaptor Protein ◽  
Annexin V ◽  
Erythropoietin Receptor ◽  
Erk Pathway ◽  
Biological Functions ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells ◽  
Survival Signal ◽  
Survival Signals

Abstract Erythropoietin (EPO) is required for the survival, proliferation and differentiation of erythroid progenitor cells. The scaffolding adaptor protein Grb2-associated binder-1 (Gab1) is tyrosine phosphorylated upon stimulation of EPO in several cell lines and erythroid progenitor cells, and interacts with signaling molecules such as SHP2 phosphatase and the p85 subunit of phosphatidylinositol 3-kinase (PI3K). However, biological functions of Gab1 in EPO receptor (EPOR)-mediated signaling has not yet been established. In this study, to explore the biological functions of Gab1 in vivo, Gab1-deficient F-36P human erythroleukemia cells were generated by means of transfection of the expression vector of siRNA against Gab1. WST-1 assay revealed that growth of Gab1-deficient F-36P cells was reduced to 61% and 77%, respectively, 5 days after incubation with lower concentrations of EPO (0.001 and 0.01 ng/ml), compared with that of mock-transfected F-36P (F-36P-mock) cells. In contrast, growth of Gab1-deficient F-36P cells at sufficient concentration of EPO (10 ng/ml) was similar to that of F-36P-mock cells. Analysis of apoptosis by flow cytometry using FITC-labeled annexin-V showed that the percentage of annexin-V-positive apoptotic cells in Gab1-deficient F-36P and F-36P-mock cells was increased to 19% and 34%, and 8% and 17%, respectively, 72 h after incubation with 0.01 and 0.001 ng/ml of EPO. These results indicate that Gab1 plays a crucial role in transducing EPOR-mediated survival signals. Next, we examined the molecular mechanism of EPOR-mediated signaling involved in survival of erythroid cells through Gab1. Western blot analysis showed that EPO-induced phosphorylation of threonine 202/ tyrosine 204 on Erk-1 and Erk-2 in Gab1-deficient F-36P but not in F-36P-mock cells was significantly suppressed. Interestingly, phosphorylation of serine 473 on Akt in Gab1-deficient F-36P cells in response to EPO was slightly suppressed in comparison with that in F-36P-mock cells. Therefore, Gab1-mediated survival signals appear to be mainly transmitted to downstream through activation of the Erk pathway, although the PI3K/Akt pathway may be involved in EPO-initiated survival signal transduction mediated by Gab1. Furthermore, EPO induced the association of SHP2 with EPOR in Gab1-deficient F-36P cells. Gab1 was associated with SHP2 in EPO-treated F-36P cells. In addition, Gab1 was constitutively associated with Grb2 in F-36P cells. Taken together, EPO induces the recruitment of Gab1 to EPOR through binding of Gab1 to SHP2, which is associated with EPOR. Because the guanine nucleotide exchange factor SOS1 is known to bind to the SH3 domain of Grb2, SOS1-Grb2 complex is recruited to vicinity of Ras at the plasma membrane to activate this GTP-binding protein through the interaction of Grb2 with Gab1, leading to activation of Erk.

Erythropoietin Increases Erythropoiesis, Metabolism and Weight Loss In Mice

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 946-946
Author(s):  
Constance Tom Noguchi ◽  
Heather Marie Rogers ◽  
Li Wang ◽  
Ruifeng Teng
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Oxygen Consumption ◽  
Progenitor Cells ◽  
White Adipose Tissue ◽  
Erythropoietin Receptor ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells ◽  
Erythropoietin Treatment ◽  
Expected Increase

Abstract Erythropoietin is required for erythroid progenitor cell survival, proliferation and differentiation. Increasing evidence suggests that erythropoietin treatment in mice can stimulate erythropoiesis and also affect metabolic processes in a dose dependent manner. For example, medium to high dose erythropoietin treatment (600 U/kg or 3000 U/kg) in leptin deficient obese (ob/ob) mice three times a week for three weeks or more results in the expected increase in hematocrit as well as decrease in accumulated body fat and improved glucose tolerance. Phlebotomy to maintain normal hematocrit demonstrated that erythropoietin regulation of body weight was not dependent on increased red cell mass. In non-obese wild type C57BL/6 mice, erythropoietin treatment also demonstrated the expected increase in hematocrit as well as a 15% reduction in body weight and decreased fasting blood glucose. Erythropoietin receptor is expressed at the highest level in erythroid progenitor cells. The link between increased metabolism and erythropoietin stimulated erythroid differentiation was suggested by the increased oxygen consumption rate observed in vitro in primary cultures of erythropoietin stimulated erythroid progenitor cells. Erythropoietin also stimulated glucose uptake in differentiating erythroid progenitor cells in a dose dependent manner. Glucose uptake decreased with the down regulation of erythropoietin receptor during terminal differentiation. Relatively high erythropoietin receptor expression and erythropoietin activity that may also contribute to erythropoietin metabolic activity has been observed in non-hematopoietic mouse tissue including the hypothalamus and white adipose tissue (Teng R, Gavrilova O et al., Nat Commun 2011). The hypothalamus contributes importantly to appetite regulation and mice treated with erythropoietin exhibited a decrease in food intake compared with saline control. We found that pair-feeding decreased body weight and fat mass, and improved glucose tolerance, but no more than half that observed with erythropoietin treatment, providing evidence that erythropoietin regulation of food intake accounts for only part of the metabolic response observed with erythropoietin treatment. Adipocytes isolated from white adipose tissue in erythropoietin treated mice showed an increase in oxygen consumption compared with vehicle treated or pair-fed mice. To assess the role of direct erythropoietin response of white adipose tissue in regulation of fat mass accumulation, we engineered mice with targeted deletion of erythropoietin receptor in adipose tissue. Erythropoietin treatment gave rise to the expected increase in hematocrit but resulted in a reduced decrease in body weight compared with saline treatment. These data show that erythropoietin treatment can stimulate cell oxygen consumption and can contribute to regulation of metabolism and body weight in mice. Erythropoietin receptor expression on erythroid progenitor cells provides for erythropoietin response to promote erythropoiesis and increase cell metabolic activity including glucose uptake and oxygen consumption. In non-hematopoietic tissue, erythropoietin receptor expression further contributes to erythropoietin regulated metabolic activity such as control of food intake attributed in part to hypothalamus response and modulation of fat mass affected by direct erythropoietin response in white adipose tissue. Therefore, in addition to its critical role in promoting erythropoiesis, erythropoietin can contribute to metabolic homeostasis via its activity in erythroid tissue and beyond. Disclosures: No relevant conflicts of interest to declare.

Erythropoietin Receptor Mutations Associated With Familial Erythrocytosis Cause Hypersensitivity to Erythropoietin in the Heterozygous State

Blood ◽  
1999 ◽  
Vol 94 (7) ◽  
pp. 2530-2532 ◽  
Author(s):  
Stephanie S. Watowich ◽  
Xiaoling Xie ◽  
Ursula Klingmuller ◽  
Juha Kere ◽  
Mikael Lindlof ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Negative Control ◽  
Erythropoietin Receptor ◽  
Heterozygous State ◽  
Wild Type ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells ◽  
Swedish Family ◽  
Inherited Mutations ◽  
Low Serum

Inherited mutations in the erythropoietin receptor (EPOR) causing premature termination of the receptor cytoplasmic region are associated with dominant familial erythrocytosis (FE), a benign clinical condition characterized by hypersensitivity of erythroid progenitor cells to EPO and low serum EPO (S-EPO) levels. We describe a Swedish family with dominant FE in which erythrocytosis segregates with a new truncation in the negative control domain of the EPOR. We show that cells engineered to concomitantly express the wild-type (WT) EPOR and mutant EPORs associated with FE (FE EPORs) are hypersensitive to EPO-stimulated proliferation and activation of Jak2 and Stat5. These results demonstrate that FE is caused by hyperresponsiveness of receptor-mediated signaling pathways and that this is dominant with respect to WT EPOR signaling.

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