Erythropoiesis

2020 ◽  
pp. 5354-5359
Author(s):  
Vijay G. Sankaran
Keyword(s):  
Erythroid Cell ◽  
Congenital Defects ◽  
Fetal Life ◽  
Erythroid Progenitors ◽  
Main Site ◽  
Congenital Deficiency ◽  
Erythropoietin Production ◽  
Multistep Process ◽  
Tissue Oxygen Delivery ◽  
Main Regulator

Erythropoiesis is a highly regulated, multistep process in which stem cells, after a series of amplification divisions, generate multipotential progenitor cells, then oligo- and finally unilineage erythroid progenitors, and then morphologically recognizable erythroid precursors and mature red cells. The ontogeny of erythropoiesis involves a series of well-coordinated events during embryonic and early fetal life. In the fetus, the main site of erythropoiesis is the liver, which initially produces mainly fetal haemoglobin (HbF, α‎2γ‎2) and a small component (10–15%) of adult haemoglobin (HbA, α‎2β‎2), with the fraction of HbA rising to about 50% at birth. After birth, the site of erythroid cell production maintained throughout life is the bone marrow, with the final adult erythroid pattern (adult Hb with <1% fetal Hb) being reached a few months after birth. Regulation of erythropoiesis—the main regulator is erythropoietin, a sialoglycoprotein that is produced by interstitial cells in the kidney in response to tissue hypoxia and exerts its effect by binding to a specific receptor on erythroid burst-forming units, erythroid colony-forming units, and proerythroblasts. Abnormal erythropoietin production—anaemia can be caused by acquired or congenital deficiency in erythropoietin production, most commonly in chronic kidney disease. Impaired tissue oxygen delivery is a common cause of erythropoietin-driven secondary erythrocytosis. Some kidney cancers increase erythropoietin production and hence cause secondary erythrocytosis. Other causes of abnormal erythroid production include (1) acquired and congenital defects in erythropoietin signalling; (2) acquired and congenital defects in the transcription factors GATA1 or EKLF; (3) acquired or congenital abnormalities in ribosome synthesis or splicing factors; and (4) factors that lead to premature red cell destruction.

Erythropoiesis and the normal red cell

2010 ◽  
pp. 4367-4374
Author(s):  
Anna Rita Migliaccio ◽  
Thalia Papayannopoulou
Keyword(s):  
Stem Cells ◽  
Progenitor Cells ◽  
Yolk Sac ◽  
Red Cells ◽  
Fetal Life ◽  
Erythroid Progenitors ◽  
Fetal Haemoglobin ◽  
Main Site ◽  
Erythroid Precursors ◽  
Multistep Process

Erythropoiesis is a highly regulated, multistep process in which stem cells, after a series of amplification divisions, generate multipotential progenitor cells, then oligo- and finally unilineage erythroid progenitors, and then morphologically recognizable erythroid precursors and mature red cells. Ontogeny of erythropoiesis—this involves a series of well-coordinated events during embryonic and early fetal life: (1) embryo—the fetal yolk sac makes embryonic haemoglobins; (2) fetus—the main site of erythopoiesis is the liver, which initially produces mainly fetal haemoglobin (Hb F, ...

scholarly journals Fetal calf serum contains activities that induce fetal hemoglobin in adult erythroid cell cultures

Blood ◽  
1990 ◽  
Vol 75 (9) ◽  
pp. 1862-1869 ◽  
Author(s):  
P Constantoulakis ◽  
B Nakamoto ◽  
T Papayannopoulou ◽  
G Stamatoyannopoulos
Keyword(s):  
Cell Cultures ◽  
Fetal Calf Serum ◽  
Calf Serum ◽  
Fetal Hemoglobin ◽  
Erythroid Cell ◽  
Erythroid Progenitors ◽  
Globin Mrna ◽  
Erythroid Progenitor ◽  
Fetal Sheep ◽  
Gamma Globin

Abstract Cultures of peripheral blood or bone marrow erythroid progenitors display stimulated production of fetal hemoglobin. We investigated whether this stimulation is due to factors contained in the sera of the culture medium. Comparisons of gamma/gamma + beta biosynthetic ratios in erythroid colonies grown in fetal calf serum (FCS) or in charcoal treated FCS (C-FCS) showed that FCS-grown cells had significantly higher gamma/gamma + beta ratios. This increase in globin chain biosynthesis was reflected by an increase in relative amounts of steady- state gamma-globin mRNA. In contrast to its effect on adult cells, FCS failed to influence gamma-chain synthesis in fetal burst forming units- erythroid (BFU-E) colonies. There was a high correlation of gamma- globin expression in paired cultures done with C-FCS or fetal sheep serum. Dose-response experiments showed that the induction of gamma- globin expression is dependent on the concentration of FCS. These results indicate that FCS contains an activity that induces gamma- globin expression in adult erythroid progenitor cell cultures.

Growth and Differentiation of Human Stem Cell Factor/Erythropoietin-Dependent Erythroid Progenitor Cells In Vitro

Blood ◽  
1998 ◽  
Vol 92 (10) ◽  
pp. 3658-3668 ◽  
Author(s):  
Birgit Panzenböck ◽  
Petr Bartunek ◽  
Markus Y. Mapara ◽  
Martin Zenke
Keyword(s):  
Stem Cell ◽  
Progenitor Cells ◽  
Stem Cell Factor ◽  
Large Cell ◽  
Erythroid Cell ◽  
Erythroid Progenitors ◽  
Peripheral Blood Stem Cells ◽  
Erythroid Progenitor ◽  
Cell Numbers

Abstract Stem cell factor (SCF) and erythropoietin (Epo) effectively support erythroid cell development in vivo and in vitro. We have studied here an SCF/Epo-dependent erythroid progenitor cell from cord blood that can be efficiently amplified in liquid culture to large cell numbers in the presence of SCF, Epo, insulin-like growth factor-1 (IGF-1), dexamethasone, and estrogen. Additionally, by changing the culture conditions and by administration of Epo plus insulin, such progenitor cells effectively undergo terminal differentiation in culture and thereby faithfully recapitulate erythroid cell differentiation in vitro. This SCF/Epo-dependent erythroid progenitor is also present in CD34+ peripheral blood stem cells and human bone marrow and can be isolated, amplified, and differentiated in vitro under the same conditions. Thus, highly homogenous populations of SCF/Epo-dependent erythroid progenitors can be obtained in large cell numbers that are most suitable for further biochemical and molecular studies. We demonstrate that such cells express the recently identified adapter protein p62dok that is involved in signaling downstream of the c-kit/SCF receptor. Additionally, cells express the cyclin-dependent kinase (CDK) inhibitors p21cip1 and p27kip1 that are highly induced when cells differentiate. Thus, the in vitro system described allows the study of molecules and signaling pathways involved in proliferation or differentiation of human erythroid cells.

scholarly journals Fetal compensation of the hemolytic anemia in mice homozygous for the normoblastosis (nb) mutation

Blood ◽  
1992 ◽  
Vol 80 (8) ◽  
pp. 2122-2127 ◽  
Author(s):  
LL Peters ◽  
CS Birkenmeier ◽  
JE Barker
Keyword(s):  
Hemolytic Anemia ◽  
Messenger Rna ◽  
Disease Onset ◽  
Rapid Onset ◽  
Erythroid Cell ◽  
Recessive Mutation ◽  
Erythroid Progenitors ◽  
Adult Mice ◽  
Autosomal Recessive Mutation ◽  
Life Threatening

Abstract The mouse autosomal recessive mutation nb causes a deficiency of erythroid ankyrin and generates a life-threatening hemolytic anemia in adult mice; however, at birth, nb/nb mice appear to be robust and show no pallor. In our study, the time of disease onset was sought by comparison of nb/nb and +/? mice both in utero and postnatally. Erythroid ankyrin messenger RNA (mRNA) is expressed in fetal erythroid progenitors from normal mice, but is reduced to 10% of normal levels in mutant fetuses. Despite the deficiency of erythroid ankyrin mRNA, 16 and 18 day nb/nb fetuses have normal levels of red blood cells (RBCs) and the RBCs are morphologically normal by scanning electron microscopy. The earliest signs of any clinical anomaly are an increase in the number of circulating reticulocytes and the deposition of minor amounts of iron just before birth in the 18 day fetal nb/nb liver, suggesting that RBCs are being destroyed. Within 24 hours after birth, nb/nb neonates have a slight but significant decrease of their RBC counts. During the next 5 days, the nb/nb RBC counts decrease markedly, the reticulocyte counts assume the mutant adult levels of 60%, the erythrocytes become microcytic and fragmented, and iron deposits accumulate in the liver. The rapid onset of clinical disease postnatally, coupled with our findings that the erythroid ankyrin gene is transcribed in fetal erythroid cell precursors from normal mice, suggest that mechanisms exist in the nb/nb fetus to compensate for the erythroid ankyrin deficiency.

scholarly journals Coordination of erythropoiesis by the transcription factor c-Myb

Blood ◽  
2006 ◽  
Vol 107 (12) ◽  
pp. 4703-4710 ◽  
Author(s):  
Alexandros Vegiopoulos ◽  
Paloma García ◽  
Nikla Emambokus ◽  
Jon Frampton
Keyword(s):  
Transcription Factor ◽  
Critical Role ◽  
Leukemia Cell ◽  
Erythroid Cell ◽  
Erythroid Progenitors ◽  
Aberrant Expression ◽  
Protein Levels ◽  
Kit Receptor ◽  
Erythroid Cell Differentiation ◽  
Factor C

Abstract The involvement of the transcription factor c-Myb in promoting the proliferation and inhibition of erythroid cell differentiation has been established in leukemia cell models. The anemia phenotype observed in c-myb knockout and knockdown mice highlights a critical role for c-Myb in erythropoiesis. However, determining the reason for the failure of erythropoiesis in these mice and the precise function of c-Myb in erythroid progenitors remains elusive. We examined erythroid development under conditions of reduced c-Myb protein levels and report an unexpected role for c-Myb in the promotion of commitment to the erythroid lineage and progression to erythroblast stages. c-myb knockdown erythroid colony-forming unit (CFU-E) stage progenitors displayed an immature phenotype and aberrant expression of several hematopoietic regulators. To extend our findings, we analyzed the response of normal enriched erythroid progenitors to inducible disruption of a floxed c-myb allele. In agreement with the c-myb knockdown phenotype, we show that c-Myb is strictly required for expression of the c-Kit receptor in erythroid cells.

Distinct Functions of Erythropoietin and Stem Cell Factor Are Linked to Activation of p70S6/mTOR Kinase Signaling Pathway in Primary Erythroid Progenitors.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2175-2175
Author(s):  
Amittha Wickrema ◽  
Uddin Shahab ◽  
Jeong Ah-Kang ◽  
Ying Zhou ◽  
Koen van Besien ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Stem Cell ◽  
Signaling Pathway ◽  
Colony Formation ◽  
Stem Cell Factor ◽  
Protein Translation ◽  
Erythroid Cell ◽  
Nuclear Fraction ◽  
Erythroid Progenitors ◽  
Akt Kinase

Abstract Erythropoietin (Epo) and stem cell factor (SCF) guide erythroid cell maturation by exerting their effects at various stages of differentiation. Distinct and overlapping functions of these two growth factors have been well characterized. However, signaling pathways responsible for the antiapoptotic function of Epo and the proliferative function of SCF has not been fully characterized. Especially activation of common upstream signaling elements PI3-kinase, Akt kinase and phosphorylation/inactivation of forkhead transcription factors by both Epo and SCF bring about distinct functional outcomes have not been understood. In the present study we examined the activation of p70S6/mTOR pathway by Epo and SCF in CD34-derived primary erythroid progenitors. Our results provide evidence for activation of p70S6 kinase and mTOR by SCF but not by Epo or IGF-1 (insulin-like growth factor-1). We also show that only SCF phosphorylates protein translational regulatory proteins, 4E-BP1 and S6 ribosomal protein suggesting its involvement in promoting protein translation. Furthermore, we demonstrate that inhibition of mTOR by rapamycin results in reduction in erythroid cell proliferation and colony-formation under steady state culture conditions demonstrating the involvement of downstream signaling elements in the PI3/Akt kinase pathway in cell proliferation apart from its antiapoptotic signal. The reduction of both BFU-E and CFU-GM colony formation indicated that rapamycin also affects early hematopoietic cells. Examination of a parallel pathway involving signaling element Mnk1 showed that both Mnk1 and its downstream target eIF4E are not phosphorylated in response to SCF or Epo. However, these protein were constitutively phosphorylated in primary erythroid progenitors. Interestingly, we also found that during the proliferative phase of erythroid differentiation mTOR is mostly detected in the cytoplasmic fraction of the cells whereas during terminal phase of differentiation mTOR is detected in the nuclear fraction. These results suggest that mTOR may have additional functions associated with chromatin remodeling in erythroid progenitors, which occur prior to enucleation. Taken together, our data provide a mechanism for how distinct functions of Epo and SCF are accomplished through selective use of a common signaling pathway explaining in part how functional diversity is acheived.

Frascati , a Mitochondrial Solute Transporter, and Its Role in Vertebrate Erythropoiesis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 49-49
Author(s):  
Barry H. Paw ◽  
George C. Shaw ◽  
John J. Cope ◽  
Kenneth Corson ◽  
Candace Hersey ◽  
...  
Keyword(s):  
Positional Cloning ◽  
Heme Biosynthesis ◽  
Developmental Expression ◽  
Deficiency Anemia ◽  
Congenital Defects ◽  
Iron Dextran ◽  
Erythroid Progenitors ◽  
Over Expression ◽  
Transporter Family ◽  
Solute Transporter

Abstract Acquired and congenital defects in iron metabolism from either deficiency or excess are one of the most common human diseases. Here we present the characterization of the zebrafish frascati mutation, which results in a profound hypochromic anemia and a developmental arrest at the pro-erythroblast stage. Using a positional cloning strategy, we have identified the gene disrupted frascati in mutants as a novel member of the mitochondrial solute transporter family. Members of this family of solute carriers have related tripartite sequence and structure. They function in transporting various metabolites and substrates across the inner mitochondrial membrane. We have verified the identity of the gene in zebrafish by the following criteria: (a) tissue-restricted expression in erythroid progenitors, (b) identification of missense mutations from the frascati five alleles, (c) rescue of anemia by over-expression frascati of cRNA in mutant embryos, and (d) mimicry of anemia using inactivating antisense morpholinos in wildtype embryos. We have also identified the functional ortholog in the mouse which has an analogous tissue and developmental expression pattern. The frascati ortholog in the mouse is highly expressed in fetal liver and adult bone marrow and spleen. The murine frascati transcript and protein are induced during terminal erythroid differentiation in MEL cells treated with either DMSO or HMBA. The over-expression of the mouse frascati cRNA in zebrafish frascati mutant embryos rescued their anemia with equal efficacy as the zebrafish clone. Given the identity of the gene and the requirement for iron in heme biosynthesis in the mitochondria of the developing erythron, we injected exogenous iron-dextran into frascati embryos. The embryos injected with iron-dextran were allowed to develop to 3 days post-fertilization, then stained for hemoglobinized cells with o-dianisidine and genotyped. Using this assay, the anemia caused by frascati the mutation could be partially rescued with exogenous iron supplementation. We therefore propose that the frascati gene functions as the essential transporter for iron importation into the mitochondria for heme biosynthesis and subsequent hemoglobin production in developing erythroid progenitors. Insight into the function of frascati the gene will be directly relevant to our understanding of human disorders of iron deficiency anemia and iron-overload sideroblastic anemia.

Dynamic Change in the Stochiometry of ETO2 and SCL Governs the Transition to Terminal Differentiation in Erythroid Progenitors.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1169-1169
Author(s):  
Julie A. Lambert ◽  
Nicolas Goardon ◽  
Patrick Rodriguez ◽  
Sabine Herblot ◽  
Pierre Thibault ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Chromatin Immunoprecipitation ◽  
Target Genes ◽  
Terminal Differentiation ◽  
Erythroid Differentiation ◽  
Erythroid Cell ◽  
Erythroid Progenitors ◽  
The Core ◽  
Undifferentiated Cells

Abstract As highly proliferative erythroid progenitors commit to terminal differentiation, they also progressively undergo growth arrest. To determine the mechanisms underlying the appropriate timing of erythroid gene expression and those associated with growth cessation, we analyzed the dynamical composition of the multiprotein complex nucleated by the bHLH transcription factor SCL, a crucial regulator of erythropoiesis that absolutely requires interaction with other factors to activate transcription. In progenitor cells, the SCL complex marks a subset of erythroid specific genes (alpha-globin, P4.2, glycophorin A) that are transcribed later in differentiating cells, conducting cells toward terminal maturation. To unravel the regulation of transcription by SCL, we used tagging/proteomics approaches in two differentiation-inducible erythroid cell lines, coupled with binding assays to immobilized DNA templates and chromatin immunoprecipitation. Our analyses reveal that the core complex comprised of known proteins (SCL, GATA-1, LMO2, Ldb1 and E2A) and two additional E protein family members, HEB and E2-2, did not change with differentiation. Strikingly, this complex recruits HDAC1-2 in undifferentiated cells which were exchanged with TRRAP, a chromatin remodelling factor, upon differentiation, suggesting an epigenetic regulation of erythroid differentiation mediated by the core SCL complex. Finally, we identified the corepressor ETO2 targeted via this complex through direct interaction with E2A/HEB. In vivo, ETO2 represses the transcription of SCL target genes both in transient assays and in chromatin. During erythroid differentiation, ETO2 remains associated with the SCL complex bound to erythroid promoters. However, the stoichiometry of ETO2 and SCL/HEB changes as SCL and HEB levels increase with erythroid differentiation, both in nuclear extracts and on DNA. To determine the functional consequence of this imbalance in activator to co-repressor ratio, we delivered ETO2 siRNA in primary hematopoietic cells and found an accelerated onset of SCL target genes on induction of erythroid differentiation, and conversely, these genes were decreased following ectopic ETO2 expression. Strikingly, inhibition of ETO2 expression in erythroid progenitors arrests cell proliferation, indicating that ETO2 is required for their expansion. We therefore analyzed gene expression in purified erythroid progenitors and differentiating erythroid cells (E1-E5) and found an inverse correlation between the mRNA levels of ETO2 and cyclin-dependent kinase inhibitors. Moreover, ETO2 siRNA treatment of primary erythroid progenitors results in increased p21 CDKI and Gfi1b expression, as assessed by real-time PCR. Finally, we show by chromatin immunoprecipitation that Gfi-1b, p21 and p27, are direct targets of the SCL- ETO2 complex. We therefore conclude that ETO2 regulates the erythroid lineage fate by repressing SCL marked erythroid genes in undifferentiated cells, and by controlling the expansion of erythroid progenitors. Our study elucidates the dual function of ETO2 in the erythroid lineage and sheds light on epigenetic mechanisms coordinating red blood cell proliferation and differentiation.

Dysregulated Expression of miRNAs in Polycythemia Vera Erythroid Progenitors.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3613-3613
Author(s):  
Hana Bruchova ◽  
Amos S. Gaikwad ◽  
Joshua Mendell ◽  
Josef T. Prchal
Keyword(s):  
Gene Expression ◽  
Polycythemia Vera ◽  
Jak2 V617f ◽  
Prediction Algorithm ◽  
Erythroid Cell ◽  
Molecular Defect ◽  
Erythroid Progenitors ◽  
Hematopoietic Stem ◽  
Homogeneous Population

Abstract Polycythemia vera (PV), the most common myeloproliferative disorder, arises due to somatic mutation(s) of a single hematopoietic stem cell leading to clonal hematopoiesis. A somatic JAK2 V617F point mutation is found in over 80% of PV patients; however, it is not clear if the JAK2 V617F is the disease initiating mutation, sincethere are PV JAK2 V617F negative patients who have monoclonal hematopoiesis and erythropoietin independent erythropoiesis;in individual PV families, there are PV subjects with and without the JAK2 V617F mutation; andanalysis of clonal PV populations reveals the presence of <50 and >50% mutated JAK2 cells (Nussenzweig’ abstract this mtg), suggesting a mixed population of cells with regard to JAK2 status.In order to search for possible PV contributing molecular defect(s), we studied microRNAs (miRNAs) in a homogeneous population of in vitro expanded erythroid progenitors. MiRNAs are non-coding, small RNAs that regulate gene expression at the posttranscriptional level by direct mRNA cleavage, by translational repression, or by mRNA decay mediated by deadenylation. MiRNAs play an important regulatory role in various biological processes including human hematopoiesis. In vitro expanded erythroid progenitors were obtained from peripheral blood mononuclear cells of 5 PV patients (JAK2 V617F heterozygotes) and from 2 healthy donor controls. The cells were cultured in an erythroid-expansion medium for 21 days resulting in 70–80% homogenous erythroid cell population of identical differentiation stage. Gene expression profiling of miRNAs (Thomson, Nature Methods, 1:1, 2004) was performed using a custom microarray (Combimatrix) with 326 miRNA probes. Data were normalized by the global median method. The miRNAs with expression ratios greater than 1.5 or less than 0.5 were considered to be abnormal. Comparative analyses of controls versus PV samples revealed up-regulated expression of miR-let7c/f, miR-16, miR-451, miR-21, miR-27a, miR-26b and miR-320 and down-regulation of miR-150, miR-339 and miR-346 in PV. In addition, miR-27a, miR-26b and miR-320 were expressed only in PV. The putative targets of these miRNAs were predicted by TargetScan prediction algorithm. Up-regulated miR-let-7, miR-16 and miR-26b may modulate cyclin D2, which has an important role in G1/S transition and can be a target in the JAK2/STAT5 pathway (Walz, JBC, 281:18177, 2006). One of the putative targets of up-regulated miR-27a is EDRF1 (erythroid terminal differentiation related factor1), a positive regulator of erythroid differentiation. The BCL-6 gene is predicted to be the target of miR-339 and miR-346, and its activation blocks cellular differentiation. MiR-16 is known to be down-regulated in CLL, where it targets anti-apoptotic BCL-2; in contrast, we show that miR-16 is up-regulated in PV erythroid cells. We identified differentially expressed miRNAs in PV which target genes involved in the JAK/STAT pathway or genes that are modulated by JAK2 downstream molecules. This study indicates that miRNA dysregulation may play an important role in erythropoietic differentiation and proliferation in PV. Expression analyses of these miRNAs in a larger set of PV samples, using quantitative Real-Time-PCR, are in progress. Further, earlier erythroid and pluripotent hematopoietic progenitors are also being analyzed.

Role for BH3-Only Protein NOXA In Growth-Factor Deprivation and Early Erythropoiesis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4235-4235
Author(s):  
Christian R. Geest ◽  
Felix M. Wensveen ◽  
Sten F.W.M. Libregts ◽  
Alex M. de Bruin ◽  
Ingrid A.M. Derks ◽  
...  
Keyword(s):  
Growth Factor ◽  
Blood Cell ◽  
Red Blood Cell ◽  
Erythroid Cell ◽  
Erythroid Progenitors ◽  
Erythroid Progenitor ◽  
Apoptosis Pathway ◽  
Cell Production ◽  
Growth Factor Deprivation ◽  
Redundant Role

Abstract Abstract 4235 Red blood cell production is a strictly regulated process and homeostatic maintenance of the erythropoietic system requires equilibrium between the rate of erythroid cell production and red blood cell destruction. Hematopoietic cytokines play a crucial role in regulating expansion, differentiation and survival of erythrocyte progenitors. Shortage of growth factors triggers the mitochondrial apoptosis pathway, which is critically dependent on Bcl-2 family members. However, the contribution of this mechanism in the regulation of erythropoiesis remains ill-defined. This prompted us to screen for candidate genes involved in this process in erythroid progenitors. We found that the expression of Noxa, a pro-apoptotic Bcl-2 family member, is upregulated during erythroid differentiation and following cytokine-withdrawal in erythroid progenitor cells. Knockdown or deletion of Noxa in IL-3 dependent human and murine erythroid progenitor cell lines increased Mcl-1 levels, which correlated with markedly decreased apoptosis following cytokine withdrawal. Importantly, Noxa ablation in mice increased extra-medullary erythropoiesis, resulting in enhanced numbers of early splenic erythroblasts and circulating reticulocytes. Noxa-deficient hematopoietic progenitors were more resistant to apoptosis induced by growth factor deprivation and displayed increased colony-forming potential. In addition, combined loss of Noxa and Bim resulted in enhanced resistance of erythroid progenitors to cytokine withdrawal compared to WT or single Bim knockouts, suggesting a non-redundant role for Noxa and Bim in regulating survival of erythroid progenitors in response to cytokine deprivation. Finally, in a model of acute haemolytic anaemia, deletion of Noxa enhanced subsequent hematocrit recovery. Together, these findings identify a non-redundant role for BH3-only protein Noxa in the regulation of erythroblast survival during early erythropoiesis. Therefore, Noxa may be a novel component to control red blood cell numbers and modulation of this pathway could be envisaged in therapeutic options for treatment of anaemia. Disclosures: No relevant conflicts of interest to declare.

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