IDH1 mutation contributes to myeloid dysplasia in mice by disturbing heme biosynthesis and erythropoiesis

Isocitrate dehydrogenase (IDH) mutations are common genetic alterations in myeloid disorders, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Epigenetic changes, including abnormal histone and DNA methylation, have been implicated in the pathogenic build-up of hematopoietic progenitors, but it is still unclear whether and how IDH mutations themselves affect hematopoiesis. Here, we show that IDH1-mutant mice develop myeloid dysplasia in that these animals exhibit anemia, ineffective erythropoiesis, increased immature progenitor and erythroblast. In erythroid cells of these mice, D-2-hydroxyglutarate (D-2HG), an aberrant metabolite produced by the mutant IDH1 enzyme, inhibits oxoglutarate dehydrogenase (OGDH) activity and diminishes succinyl-CoA production. This succinyl-CoA deficiency attenuates heme biosynthesis in IDH1-mutant hematopoietic cells, thus blocking erythroid differentiation at the late erythroblast stage and the erythroid commitment of hematopoietic stem cells (HSC), while the exogenous succinyl-CoA or 5-ALA rescues erythropoiesis in IDH1-mutant erythroid cells. Heme deficiency also impairs heme oxygenase-1 (HO-1) expression, which reduces levels of important heme catabolites such as biliverdin and bilirubin. These deficits result in accumulation of excessive reactive oxygen species (ROS) that induce the cell death of IDH1-mutant erythroid cells. Our results clearly demonstrate the essential role of IDH1 in normal erythropoiesis and show how its mutation leads to myeloid disorders. Our data thus have important implications for the devising of new treatments for IDH-mutant tumors.

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Heme Oxygenase 1 Plays An Unexpected Role During Erythroid Differentiation

Blood ◽

10.1182/blood.v118.21.344.344 ◽

2011 ◽

Vol 118 (21) ◽

pp. 344-344

Author(s):

Daniel Garcia Santos ◽

Matthias Schranzhofer ◽

José Artur Bogo Chies ◽

Prem Ponka

Keyword(s):

Red Blood Cells ◽

Heme Oxygenase ◽

Blood Cells ◽

Erythroid Differentiation ◽

Heme Biosynthesis ◽

Erythroid Cell ◽

Heme Oxygenase 1 ◽

Erythroid Cells ◽

Wild Type ◽

Protein Levels

Abstract Abstract 344 Red blood cells (RBC) are produced at a rate of 2.3 × 106 cells per second by a dynamic and exquisitely regulated process known as erythropoiesis. During this development, RBC precursors synthesize the highest amounts of total organismal heme (75–80%), which is a complex of iron with protoporphyrin IX. Heme is essential for the function of all aerobic cells, but if left unbound to protein, it can promote free radical formation and peroxidation reactions leading to cell damage and tissue injury. Therefore, in order to prevent the accumulation of ‘free' heme, it is imperative that cells maintain a balance of heme biosynthesis and catabolism. Physiologically, the only enzyme capable of degrading heme are heme oxyganase 1 & 2 (HO). Red blood cells contain the majority of heme destined for catabolism; this process takes place in splenic and hepatic macrophages following erythrophagocytosis of senescent RBC. Heme oxygenase, in particular its heme-inducible isoform HO1, has been extensively studied in hepatocytes and many other non-erythroid cells. In contrast, virtually nothing is known about the expression of HO1 in developing RBC. Likewise, it is unknown whether HO1 plays any role in erythroid cell development under physiological or pathophysiological conditions. Using primary erythroid cells isolated from mouse fetal livers (FL), we have shown that HO1 mRNA and protein are expressed in undifferenetiated FL cells and that its levels, somewhat surprisingly, increase during erythropoietin-induced erythroid differentiation. This increase in HO1 can be prevented by succinylacetone (SA), an inhibitor of heme synthesis that blocks 5-aminolevulinic acid dehydratase, the second enzyme in the heme biosynthesis pathway. Moreover, we have found that down-regulation of HO1 via siRNA increases globin protein levels in DMSO-induced murine erythroleukemic (MEL) cells. Similarly, compared to wild type mice, FL cells isolated from HO1 knockout mice (FL/HO1−/−) exhibited increased globin and transferrin receptor levels and a decrease in ferritin levels when induced for differentiation with erythropoietin. Following induction, compared to wild type cells, FL/HO1−/− cells showed increased iron uptake and its incorporation into heme. We therefore conclude that the normal hemoglobinization rate appears to require HO1. On the other hand, MEL cells engineered to overexpress HO1 displayed reduced globin mRNA and protein levels when induced to differentiate. This finding suggests that HO1 could play a role in some pathophysiological conditions such as unbalanced globin synthesis in thalassemias. Disclosures: No relevant conflicts of interest to declare.

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Biology of Heme in Mammalian Erythroid Cells and Related Disorders

BioMed Research International ◽

10.1155/2015/278536 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 13

Author(s):

Tohru Fujiwara ◽

Hideo Harigae

Keyword(s):

Biosynthetic Pathway ◽

Iron Acquisition ◽

Protoporphyrin Ix ◽

Erythroid Differentiation ◽

Heme Biosynthesis ◽

Erythroid Cells ◽

Prosthetic Group ◽

Expression Of Genes ◽

Human Disorders ◽

Pathway Regulation

Heme is a prosthetic group comprising ferrous iron (Fe2+) and protoporphyrin IX and is an essential cofactor in various biological processes such as oxygen transport (hemoglobin) and storage (myoglobin) and electron transfer (respiratory cytochromes) in addition to its role as a structural component of hemoproteins. Heme biosynthesis is induced during erythroid differentiation and is coordinated with the expression of genes involved in globin formation and iron acquisition/transport. However, erythroid and nonerythroid cells exhibit distinct differences in the heme biosynthetic pathway regulation. Defects of heme biosynthesis in developing erythroblasts can have profound medical implications, as represented by sideroblastic anemia. This review will focus on the biology of heme in mammalian erythroid cells, including the heme biosynthetic pathway as well as the regulatory role of heme and human disorders that arise from defective heme synthesis.

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IDH1 Targeting as a New Potential Option for Intrahepatic Cholangiocarcinoma Treatment—Current State and Future Perspectives

Molecules ◽

10.3390/molecules25163754 ◽

2020 ◽

Vol 25 (16) ◽

pp. 3754

Author(s):

Fabiana Crispo ◽

Michele Pietrafesa ◽

Valentina Condelli ◽

Francesca Maddalena ◽

Giuseppina Bruno ◽

...

Keyword(s):

Treatment Options ◽

Point Mutations ◽

Genetic Alterations ◽

Idh1 Mutation ◽

Primary Malignancy ◽

Pharmacological Agents ◽

Molecular Alterations ◽

Starting Point ◽

Metabolic Remodeling ◽

Mutant Idh1

Cholangiocarcinoma is a primary malignancy of the biliary tract characterized by late and unspecific symptoms, unfavorable prognosis, and few treatment options. The advent of next-generation sequencing has revealed potential targetable or actionable molecular alterations in biliary tumors. Among several identified genetic alterations, the IDH1 mutation is arousing interest due to its role in epigenetic and metabolic remodeling. Indeed, some IDH1 point mutations induce widespread epigenetic alterations by means of a gain-of-function of the enzyme, which becomes able to produce the oncometabolite 2-hydroxyglutarate, with inhibitory activity on α-ketoglutarate-dependent enzymes, such as DNA and histone demethylases. Thus, its accumulation produces changes in the expression of several key genes involved in cell differentiation and survival. At present, small-molecule inhibitors of IDH1 mutated enzyme are under investigation in preclinical and clinical phases as promising innovative treatments for IDH1-mutated intrahepatic cholangiocarcinomas. This review examines the molecular rationale and the results of preclinical and early-phase studies on novel pharmacological agents targeting mutant IDH1 in cholangiocarcinoma patients. Contextually, it will offer a starting point for discussion on combined therapies with metabolic and epigenetic drugs, to provide molecular support to target the interplay between metabolism and epigenetics, two hallmarks of cancer onset and progression.

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SCL/TAL1 Regulates Erythropoietin Receptor Expression.

Blood ◽

10.1182/blood.v108.11.1195.1195 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1195-1195

Author(s):

Heather M. Rogers ◽

Xiaobing Yu ◽

Constance Tom Noguchi

Keyword(s):

Erythroid Differentiation ◽

Erythropoietin Receptor ◽

Receptor Expression ◽

Binding Motif ◽

Erythroid Cells ◽

Hematopoietic Stem ◽

Mild Anemia ◽

Adult Mice ◽

High Level

Abstract The basic-helix-loop-helix transcription factor SCL/TAL1, is required for erythropoiesis during development, and conditional deletion in adult hematopoiesis results in hematopoietic stem cells with a competitive repopulation disadvantage and defective erythropoiesis in vitro. However, adult mice with a conditional SCL/TAL1 deletion survive with mild anemia, suggesting defective erythroid proliferation and indicating that SCL/TAL1 is important, but not essential in mature red blood cell production. We find that during erythroid differentiation of primary human hematopoietic CD34+ cells, SCL/TAL1 expression peaks at day 8–10 following erythropoietin (EPO) stimulation, concomitant with peak expression of GATA-1 and EKLF. Treatment with SCL/TAL1 antisense oligonucleotides during erythroid differentiation markedly decreases erythroid differentiation as indicated by decreased expression of GATA-1 and both b- and g-globin expression, along with the absence of the characteristic decrease in GATA-2. Microarray analysis of erythroid cells overexpressing SCL/TAL1 indicate increased gene expression for b- and g-globin, and other genes related to erythropoiesis including EPO receptor (EPO-R), and these results are confirmed in stable cell lines with increasing SCL/TAL1 expression. Examination of EPO-R transcription regulation indicates that E-boxes in the 5′ UTR can bind SCL/TAL1 in vitro and, in addition to the GATA-1 binding motif, provide transcription activity in reporter gene assays. These data indicate that in addition to the importance of SCL/TAL1 DNA binding for proliferation of BFU-E and expression of glycophorin A and protein 4.2, SCL/TAL1 is also necessary for high level expression of EPO-R. Reduction in EPO-R expression likely contributes to the anemia associated with the conditional adult deletion of SCL/TAL1 and to the proliferative defect of erythroid cells observed in vitro. Early expression of SCL/TAL1 in hematopoietic cells may activate expression of EPO-R prior to EPO stimulation of erythropoiesis and induction of GATA-1.

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Studies on Heme Oxygenase 1 During Erythroid Differentiation

Blood ◽

10.1182/blood.v116.21.4254.4254 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4254-4254

Author(s):

Daniel Garcia Santos ◽

Jesse Eisenberg ◽

Matthias Schranzhofer ◽

Prem Ponka

Keyword(s):

Aminolevulinic Acid ◽

Conflicts Of Interest ◽

Tissue Injury ◽

Erythroid Differentiation ◽

The Body ◽

Cellular Damage ◽

Erythroid Cell ◽

Heme Oxygenase 1 ◽

Erythroid Cells ◽

Murine Erythroleukemia

Abstract Abstract 4254 Heme is indispensable for the function of all aerobic cells as a prosthetic group of innumerable proteins. However, “free heme” (uncommitted) can initiate the formation of free radicals and cause lipid peroxidation, which can lead to cellular damage and tissue injury. Therefore, the rate of heme biosynthesis and catabolism must be well balanced by tight control mechanisms. The highest amounts of organismal heme (75-80%) are present in circulating red blood cells (RBC), whose precursors synthesize heme with rates that are at least one order of magnitude higher (on the per cell basis) than those in the liver – the second most active heme producer in the body. The degradation of heme is exclusively carried out by heme oxygenases 1 and 2 (HO1 and HO2), which catalyze the rate-limiting step in the oxidative degradation of heme. Although the heme-inducible HO isoform, HO1, has been extensively studied in hepatocytes and many other non-erythroid cells, virtually nothing is known about the expression of HO1 in developing RBC. Similarly, it is unknown whether HO1 plays any role in erythroid cell development under physiological or pathophysiological conditions. Using both a murine erythroleukemia cell line (MEL) and primary erythroid cells isolated from mouse fetal livers, we have demonstrated that during erythroid differentiation HO1 is up-regulated at both mRNA and protein levels. This increase in HO1 can be prevented by succinylacetone (SA), an inhibitor of heme synthesis that blocks 5-aminolevulinic acid dehydratase. These data suggest that in developing RBC, in addition to the continuous assembly of heme with globin chains, there is an increase in levels of uncommitted heme, which upregulates HO1 expression. Additionally, we have shown that down-regulation of HO1 via siRNA increased hemoglobinization in differentiating MEL cells. In contrast, induction of HO1 expression by NaAsO2 reduced the hemoglobinization of MEL cells. This effect could be reversed to control levels by the addition of HO1 inhibitor tin-protophorphyrin (SnPP). These results show that in differentiating erythroid cells the balance between levels of heme and HO1 have to be tightly regulated to maintain hemoglobinization at appropriate levels. Our results lead us to propose that disturbances in HO1 expression could play a role in some pathophysiological conditions such as thalassemias. Disclosures: No relevant conflicts of interest to declare.

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In VitroLarge Scale Production of Human Mature Red Blood Cells from Hematopoietic Stem Cells by Coculturing with Human Fetal Liver Stromal Cells

BioMed Research International ◽

10.1155/2013/807863 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 7

Author(s):

Jiafei Xi ◽

Yanhua Li ◽

Ruoyong Wang ◽

Yunfang Wang ◽

Xue Nan ◽

...

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

Cord Blood ◽

Red Blood Cells ◽

Stromal Cells ◽

Blood Cells ◽

Fetal Liver ◽

Erythroid Differentiation ◽

Erythroid Cells ◽

Hematopoietic Stem

In vitromodels of human erythropoiesis are useful in studying the mechanisms of erythroid differentiation in normal and pathological conditions. Here we describe an erythroid liquid culture system starting from cord blood derived hematopoietic stem cells (HSCs). HSCs were cultured for more than 50 days in erythroid differentiation conditions and resulted in a more than 109-fold expansion within 50 days under optimal conditions. Homogeneous erythroid cells were characterized by cell morphology, flow cytometry, and hematopoietic colony assays. Furthermore, terminal erythroid maturation was improved by cosculturing with human fetal liver stromal cells. Cocultured erythroid cells underwent multiple maturation events, including decrease in size, increase in glycophorin A expression, and nuclear condensation. This process resulted in extrusion of the pycnotic nuclei in up to 80% of the cells. Importantly, they possessed the capacity to express the adult definitiveβ-globin chain upon further maturation. We also show that the oxygen equilibrium curves of the cord blood-differentiated red blood cells (RBCs) are comparable to normal RBCs. The large number and purity of erythroid cells and RBCs produced from cord blood make this method useful for fundamental research in erythroid development, and they also provide a basis for future production of available RBCs for transfusion.

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Preeclampsia is Associated with Sex-Specific Transcriptional and Proteomic Changes in Fetal Erythroid Cells

International Journal of Molecular Sciences ◽

10.3390/ijms20082038 ◽

2019 ◽

Vol 20 (8) ◽

pp. 2038 ◽

Cited By ~ 2

Author(s):

Zahra Masoumi ◽

Gregory E. Maes ◽

Koen Herten ◽

Álvaro Cortés-Calabuig ◽

Abdul Ghani Alattar ◽

...

Keyword(s):

Mammalian Target Of Rapamycin ◽

Erythroid Differentiation ◽

Erythroid Cells ◽

Surface Adhesion ◽

Hematopoietic Stem ◽

Ampk Signaling ◽

Placental Dysfunction ◽

Transcriptional Changes ◽

Amp Activated Protein Kinase

Preeclampsia (PE) has been associated with placental dysfunction, resulting in fetal hypoxia, accelerated erythropoiesis, and increased erythroblast count in the umbilical cord blood (UCB). Although the detailed effects remain unknown, placental dysfunction can also cause inflammation, nutritional, and oxidative stress in the fetus that can affect erythropoiesis. Here, we compared the expression of surface adhesion molecules and the erythroid differentiation capacity of UCB hematopoietic stem/progenitor cells (HSPCs), UCB erythroid profiles along with the transcriptome and proteome of these cells between male and female fetuses from PE and normotensive pregnancies. While no significant differences were observed in UCB HSPC migration/homing and in vitro erythroid colony differentiation, the UCB HSPC transcriptome and the proteomic profile of the in vitro differentiated erythroid cells differed between PE vs. normotensive samples. Accordingly, despite the absence of significant differences in the UCB erythroid populations in male or female fetuses from PE or normotensive pregnancies, transcriptional changes were observed during erythropoiesis, particularly affecting male fetuses. Pathway analysis suggested deregulation in the mammalian target of rapamycin complex 1/AMP-activated protein kinase (mTORC1/AMPK) signaling pathways controlling cell cycle, differentiation, and protein synthesis. These results associate PE with transcriptional and proteomic changes in fetal HSPCs and erythroid cells that may underlie the higher erythroblast count in the UCB in PE.

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Functional Analysis of FOXO3A Involved in Erythroid Differentiation

Blood ◽

10.1182/blood.v120.21.4731.4731 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4731-4731

Author(s):

Hai Wang ◽

Yadong Yang ◽

Hongzhu QU ◽

Xiuyan Ruan ◽

Zhaojun Zhang ◽

...

Keyword(s):

Stem Cells ◽

Conflicts Of Interest ◽

Es Cells ◽

Embryonic Stem ◽

Erythroid Differentiation ◽

Expression Level ◽

Homologous Gene ◽

Erythroid Cells ◽

Hematopoietic Stem ◽

Central Node

Abstract Abstract 4731 FOX (Forkhead box) proteins are a family of transcription factors that emerged as playing an important role in the embryonic development, cell cycle, carbohydrate and fatty acid metabolism and immune response. It was found that FOXO3A (also known as FOXO3) involved in erythroid differentiation, yet the mechanism for regulating hematopoietic stem cells (HSCs) differentiation is unknown. We analyzed the dynamics of genome-wide transcriptome (mRNA-Seq) of human undifferentiated embryonic stem cells (HESC), erythroid cells derived from ES cells (ESER), human fetal erythroid liver cells (FLER) and peripheral CD34+derived erythroid cells (PBER) using high throughput sequencing technology. The transcriptome analysis showed that FOXO3 was barely expression in HESC while was observably up-regulated in ESER. However, FOXO3 was down-regulated in FLER and PBER compare with ESER, the erythroid cells at early developmental stage. We presumed that FOXO3 plays an important role in primitive erythropoiesis and built up the interactions network in which FOXO3 acts as a central node by Gene Ontology (GO), correlation analysis and Ingenuity Pathways Analysis (IPA). In addition, we analyzed the profiles of histone methylation in the four types of cells by ChIP-Seq to study the chromatin conformation in the vicinity of FOXO3. More histone 3 lysine 4 (H3K4) trimethylation was found near the promoter region of FOXO3 in ESER compared with the other cells, which is coincided with the mRNA-seq results. We performed a series of experiment to identify the roles of FOXO3 in regulating erythroid differentiation. The results showed that the expression level of ε and γ globin were up-regulated in FOXO3-over-expressed 293T and Hela cells and the expression level of FOXO1 and CAT in predicted network were increased by quantitative real-time PCR detection. In addition, when FOXO3 knocked down in K562 cells, the expression level of ε and γ globin were down-regulated. The expression level of CAT, BCL2L1 and other factors in predicted network, were also decreased. These results indicate FOXO3 plays an important role in globin expression and identify the credibility of our predicted networks in which FOXO3 acts as a central node. FOXO3 binding sites (GTAAACA or ATAAACA) were predicted on the upstream of CAT and BCL2L1. We are trying to prove CAT or BCL2L1 is a direct FOXO3 target in vitro and in vivo. In conclusion, we have demonstrated FOXO3 plays a key role in erythroid differentiation and globin expression. We will further determine the enriched profiles of FOXO3 by ChIP-seq in HESC, ESER, FLER and PBER to find more targets of FOXO3. Since the zebrafish is a powerful model system for investigating vertebrate hematopoiesis. We will identify the role of Foxo3b, the homologous gene of human FOXO3, in erythroid differentiation and study the dynamic transcriptomes of Foxo3b morphants in zebrafish. We are trying to make a whole picture to elaborate the molecular mechanism of FOXO3 involved in regulation of erythroid differentiation. Disclosures: No relevant conflicts of interest to declare.

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LSD1 Plays an Important Role in GATA Switch during Erythroid Differentiation

Blood ◽

10.1182/blood.v122.21.4846.4846 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4846-4846

Author(s):

Yue Jin ◽

Yidi Guo ◽

Dongxue Liang ◽

Yue Li ◽

Zhe Li ◽

...

Keyword(s):

Molecular Mechanisms ◽

Conflicts Of Interest ◽

Es Cells ◽

Regulatory Element ◽

Erythroid Differentiation ◽

Erythroid Cell ◽

Erythroid Cells ◽

Hematopoietic Stem ◽

Mouse Es Cells ◽

Murine Erythroleukemia

Abstract GATA factors play important role in hematopoiesis. In particular, GATA2 is critical for maintenance of hematopoietic stem and progenitor cells (HS/PCs) and GATA1 is required for erythropoiesis. GATA1 and GATA2 are expressed in reciprocal patterns during erythroid differentiation. It was shown that GATA1 occupied the -2.8Kb regulatory element and mediated repression of the GATA2 promoter in terminally differentiating erythroid cells. However, the detailed molecular mechanisms that control the enhancer/promoter activities of the GATA2 gene remain to be elucidated. In this report, we found that LSD1 and TAL1 co-localize at GATA2 1S promoter through ChIP and double-ChIP assays in murine erythroleukemia (MEL) cells. To further test whether LSD1 and its mediated H3K4 demethylation is important for repression of the GATA2 gene during erythroid differentiation, we silenced LSD1 expression in both MEL cells and mouse ES cells using retrovirus mediated shRNA knockdown and induced them to differentiate into erythroid cells with DMSO and EPO, respectively. GATA2 expression was elevated while the level of GATA1 was repressed by RT-qPCR. Furthermore, consistent with the GATA witch hypothesis, ChIP analysis revealed that the levels of H3K4me2 were increased at the GATA2 1S promoter. In addition, knock-down of LSD1 in MEL cells results in inhibition of erythroid cell differenciation and attenuation of MEL cell proliferation and survival. Thus, our data reveal that LSD1 involved in control of terminal erythroid differentiation by regulating GATA switch. The LSD1 histone demethylase complex may be recruited to the GATA2 1S promoter by interacting with TAL1. The H3K4 demethylation activity of LSD1 leads to downregulation of the active H3K4m2 mark at the GATA2 promoter that alters chromatin structure and represses transcription of the GATA2 genes. Disclosures: No relevant conflicts of interest to declare.

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Requirements for survivin in terminal differentiation of erythroid cells and maintenance of hematopoietic stem and progenitor cells

Journal of Experimental Medicine ◽

10.1084/jem.20062395 ◽

2007 ◽

Vol 204 (7) ◽

pp. 1603-1611 ◽

Cited By ~ 73

Author(s):

Cindy G. Leung ◽

Yanfei Xu ◽

Bretton Mularski ◽

Hui Liu ◽

Sandeep Gurbuxani ◽

...

Keyword(s):

Steady State ◽

Spindle Assembly Checkpoint ◽

Survivin Expression ◽

Erythroid Differentiation ◽

Inhibitor Of Apoptosis ◽

Specific Gene ◽

Erythroid Cells ◽

Hematopoietic Stem ◽

Apoptosis Protein ◽

High Level

Survivin, which is the smallest member of the inhibitor of apoptosis protein (IAP) family, is a chromosomal passenger protein that mediates the spindle assembly checkpoint and cytokinesis, and also functions as an inhibitor of apoptosis. Frequently overexpressed in human cancers and not expressed in most adult tissues, survivin has been proposed as an attractive target for anticancer therapies and, in some cases, has even been touted as a cancer-specific gene. Survivin is, however, expressed in proliferating adult cells, including human hematopoietic stem cells, T-lymphocytes, and erythroid cells throughout their maturation. Therefore, it is unclear how survivin-targeted anticancer therapies would impact steady-state blood development. To address this question, we used a conditional gene-targeting strategy and abolished survivin expression from the hematopoietic compartment of mice. We show that inducible deletion of survivin leads to ablation of the bone marrow, with widespread loss of hematopoietic progenitors and rapid mortality. Surprisingly, heterozygous deletion of survivin causes defects in erythropoiesis in a subset of the animals, with a dramatic reduction in enucleated erythrocytes and the presence of immature megaloblastic erythroblasts. Our studies demonstrate that survivin is essential for steady-state hematopoiesis and survival of the adult, and further, that a high level of survivin expression is critical for proper erythroid differentiation.

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