Proliferative Defect but Normal Transcriptional Response to Erythropoietin in Diamond Blackfan Anemia Erythroid Progenitor Cells in 2-Phase Erythroid Culture.

Abstract Diamond Blackfan anaemia (DBA) is a rare congenital red cell aplasia, characterised by a steroid responsive intrinsic erythropoietic failure. Mutations affecting RPS19 are found in up to 25% of DBA, but the pathophysiological link between ribosomal gene haploinsufficiency and the specific erythroid phenotype of DBA remains elusive. One potential mechanism is that ribosomal insufficiency might affect the level of expression of critical erythroid proteins, resulting in a block in terminal erythroid differentiation and expansion. The aim of this study was to elucidate the cellular and molecular events occurring in response to erythropoietin (EPO) in DBA. We applied a 2-phase erythroid culture system in which we have previously demonstrated a consistent and profound failure of erythroid expansion in DBA cultures, localised to early in the second EPO-dependent phase of culture. The timing of the onset of proliferation in response to EPO was studied by tetrazolium dye assay of enriched erythroid progenitor cells in phase II of culture. An increase in cell number was detectable following 72hrs of EPO exposure in DBA (n=5) as well as control cultures, but with a subsequently slower proliferation rate in DBA. The proliferation rate of both DBA and control cells was enhanced by the addition of dexamethasone. Transcriptional profiles of control and DBA erythroid progenitors were then compared by microarray analysis after 24hrs exposure to EPO. Cy3/Cy5 labelled aRNA was competitively hybridised on an in-house array containing 395 transcript exon identifiers in ENSEMBL. The results showed little difference in expression between control and DBA after 24hrs of EPO exposure, the only significant changes being in the expression of just 4 of the 251 genes expressed above background (CDKN2D, TNFRSF6, MAPKK and CXCR), which were upregulated in DBA (p<0.0001 on t-test analysis). The gene expression profile from 0–96 hrs following EPO exposure was then studied in control and DBA (n=3) erythroid progenitors by real time PCR. There was little change in the first 48hr of exposure to EPO. At 72hrs the expression of both EPOR and α-GLOBIN was increased 3–6 fold in both DBA and controls in comparison with pre-EPO, confirming the occurrence of an erythroid-specific transcriptional response to EPO in DBA erythroid progenitors. These results are consistent with a qualitatively normal onset of terminal erythroid maturation in DBA, rather than a block in differentiation, and tend to favour an alternative hypothesis that the erythroid failure in DBA is the result of ribosomal insufficiency at the simultaneous onset of both rapid cell proliferation and a high rate of globin synthesis. In keeping with this, the expression of RPS19 showed 1.5–2 fold increase at 72hrs after EPO exposure, with 3.5 fold increase in the presence of dexamethasone, with equivalent results in both DBA and controls. We now aim to study translational and cell cycle events during this important wave of erythroid proliferation to further elucidate the molecular basis for the specific erythroid defect in DBA, despite the ubiquitous cellular requirement for ribosomal biogenesis.

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

Molecular and Cellular Biology ◽

10.1128/mcb.14.4.2266 ◽

1994 ◽

Vol 14 (4) ◽

pp. 2266-2277 ◽

Cited By ~ 33

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.

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Erythropoietin can promote erythroid progenitor survival by repressing apoptosis through Bcl-XL and Bcl-2

Blood ◽

10.1182/blood.v88.5.1576.1576 ◽

1996 ◽

Vol 88 (5) ◽

pp. 1576-1582 ◽

Cited By ~ 243

Author(s):

M Silva ◽

D Grillot ◽

A Benito ◽

C Richard ◽

G Nunez ◽

...

Keyword(s):

Progenitor Cells ◽

Apoptotic Cell ◽

Ectopic Expression ◽

Erythroid Differentiation ◽

Erythroid Progenitors ◽

Erythroid Progenitor ◽

Survival Factor ◽

Erythroid Progenitor Cells ◽

Survival Signal ◽

Proliferation And Differentiation

Abstract Erythropoietin (Epo), the hormone that is the principal regulator of red blood cell production, interacts with high-affinity receptors on the surface of erythroid progenitor cells and maintains their survival. Epo has been shown to promote cell viability by repressing apoptosis; however, the molecular mechanism involved is unclear. In the present studies we have examined whether Epo acts as a survival factor through the regulation of the bcl-2 family of apoptosis-regulatory genes. We addressed this issue in HCD-57, a murine erythroid progenitor cell line that requires Epo for proliferation and survival. When HCD-57 cells were cultured in the absence of Epo, Bcl-2 and Bcl-XL but not Bax were downregulated, and the cells underwent apoptotic cell death. HCD-57 cells infected with a retroviral vector encoding human Bcl-XL or Bcl-2 rapidly stopped proliferating but remained viable in the absence of Epo. Furthermore, endogenous levels of bcl-2 and bcl-XL were downregulated after Epo withdrawal in HCD-57 cells that remained viable through ectopic expression of human Bcl-XL, further indicating that Epo specifically maintains the expression of bcl-2 and bcl-XL. We also show that HCD-57 rescued from apoptosis by ectopic expression of Bcl-XL can undergo erythroid differentiation in the absence of Epo, demonstrating that a survival signal but not Epo itself is necessary for erythroid differentiation of HCD-57 progenitor cells. Thus, we propose a model whereby Epo functions as a survival factor by repressing apoptosis through Bcl-XL and Bcl-2 during proliferation and differentiation of erythroid progenitors.

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Identification of Increased Protein Tyrosine Phosphatase Activity in Polycythemia Vera Erythroid Progenitor Cells

Blood ◽

10.1182/blood.v90.2.651 ◽

1997 ◽

Vol 90 (2) ◽

pp. 651-657 ◽

Cited By ~ 41

Author(s):

Xingwei Sui ◽

Sanford B. Krantz ◽

Zhizhuang Zhao

Keyword(s):

Polycythemia Vera ◽

Progenitor Cells ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Gel Filtration ◽

Erythroid Progenitors ◽

Erythroid Progenitor ◽

Normal Cells ◽

Protein Tyrosine ◽

Erythroid Progenitor Cells

Abstract Polycythemia vera (PV) is a clonal hematologic disease characterized by hyperplasia of the three major bone marrow lineages. PV erythroid progenitor cells display hypersensitivity to several growth factors, which might be caused by an abnormality of tyrosine phosphorylation. In the present study, we have investigated protein tyrosine phosphatase (PTP) activity in highly purified erythroid progenitor cells and found that the total PTP activity in the PV cells was twofold to threefold higher than that in normal cells. Protein separation on anion-exchange and gel-filtration columns showed that the increased activity was due to a major PTP eluted at approximately 170 kD. This enzyme was sensitive to PTP inhibitors and it did not cross-react with antibodies to SHP-1, SHP-2, or CD45. Subcellular fractionation showed that the PTP localized with the membrane fraction, where its activity was increased by threefold in PV erythroid progenitors when compared with normal cells. As the erythroid progenitors progressively matured, activity of the PTP declined rapidly in the normal cells but at a much slower rate in the PV cells. These studies suggest that a potentially novel membrane or membrane-associated PTP, representing a major PTP activity, may have an important role in proliferation and/or survival of human erythroid progenitors and that its hyperactivation in PV erythroid progenitors might be responsible for the increased erythropoiesis in PV patients.

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PU.1 determines the self-renewal capacity of erythroid progenitor cells

Blood ◽

10.1182/blood-2003-11-4089 ◽

2004 ◽

Vol 103 (10) ◽

pp. 3615-3623 ◽

Cited By ~ 79

Author(s):

Jonathan Back ◽

Andrée Dierich ◽

Corinne Bronn ◽

Philippe Kastner ◽

Susan Chan

Keyword(s):

Progenitor Cells ◽

Fluorescent Protein ◽

Erythroid Progenitors ◽

Erythroid Progenitor ◽

Self Renewal ◽

Adult Mice ◽

Erythroid Progenitor Cells ◽

Low Levels ◽

Green Fluorescent ◽

Fluorescent Protein Reporter

Abstract PU.1 is a hematopoietic-specific transcriptional activator that is absolutely required for the differentiation of B lymphocytes and myeloid-lineage cells. Although PU.1 is also expressed by early erythroid progenitor cells, its role in erythropoiesis, if any, is unknown. To investigate the relevance of PU.1 in erythropoiesis, we produced a line of PU.1-deficient mice carrying a green fluorescent protein reporter at this locus. We report here that PU.1 is tightly regulated during differentiation—it is expressed at low levels in erythroid progenitor cells and down-regulated upon terminal differentiation. Strikingly, PU.1-deficient fetal erythroid progenitors lose their self-renewal capacity and undergo proliferation arrest, premature differentiation, and apoptosis. In adult mice lacking one PU.1 allele, similar defects are detected following stress-induced erythropoiesis. These studies identify PU.1 as a novel and critical regulator of erythropoiesis and highlight the versatility of this transcription factor in promoting or preventing differentiation depending on the hematopoietic lineage.

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

Molecular and Cellular Biology ◽

10.1128/mcb.14.4.2266-2277.1994 ◽

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

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Erythropoietin can promote erythroid progenitor survival by repressing apoptosis through Bcl-XL and Bcl-2

Blood ◽

10.1182/blood.v88.5.1576.bloodjournal8851576 ◽

1996 ◽

Vol 88 (5) ◽

pp. 1576-1582 ◽

Cited By ~ 10

Author(s):

M Silva ◽

D Grillot ◽

A Benito ◽

C Richard ◽

G Nunez ◽

...

Keyword(s):

Progenitor Cells ◽

Apoptotic Cell ◽

Ectopic Expression ◽

Erythroid Differentiation ◽

Erythroid Progenitors ◽

Erythroid Progenitor ◽

Survival Factor ◽

Erythroid Progenitor Cells ◽

Survival Signal ◽

Proliferation And Differentiation

Erythropoietin (Epo), the hormone that is the principal regulator of red blood cell production, interacts with high-affinity receptors on the surface of erythroid progenitor cells and maintains their survival. Epo has been shown to promote cell viability by repressing apoptosis; however, the molecular mechanism involved is unclear. In the present studies we have examined whether Epo acts as a survival factor through the regulation of the bcl-2 family of apoptosis-regulatory genes. We addressed this issue in HCD-57, a murine erythroid progenitor cell line that requires Epo for proliferation and survival. When HCD-57 cells were cultured in the absence of Epo, Bcl-2 and Bcl-XL but not Bax were downregulated, and the cells underwent apoptotic cell death. HCD-57 cells infected with a retroviral vector encoding human Bcl-XL or Bcl-2 rapidly stopped proliferating but remained viable in the absence of Epo. Furthermore, endogenous levels of bcl-2 and bcl-XL were downregulated after Epo withdrawal in HCD-57 cells that remained viable through ectopic expression of human Bcl-XL, further indicating that Epo specifically maintains the expression of bcl-2 and bcl-XL. We also show that HCD-57 rescued from apoptosis by ectopic expression of Bcl-XL can undergo erythroid differentiation in the absence of Epo, demonstrating that a survival signal but not Epo itself is necessary for erythroid differentiation of HCD-57 progenitor cells. Thus, we propose a model whereby Epo functions as a survival factor by repressing apoptosis through Bcl-XL and Bcl-2 during proliferation and differentiation of erythroid progenitors.

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Direct Interaction with Macrophages Increases Proerythroblast Proliferation While Preserving Erythropoietin (EPO) Dependence.

Blood ◽

10.1182/blood.v108.11.1287.1287 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1287-1287

Author(s):

Melissa M. Rhodes ◽

Prapaporn Kopsombut ◽

Maurice Bondurant ◽

James O. Price ◽

Mark J. Koury

Keyword(s):

Cell Cycle ◽

Progenitor Cells ◽

Direct Interaction ◽

Erythroid Progenitors ◽

Erythroid Progenitor ◽

Erythroid Progenitor Cells ◽

Cell Counts ◽

Cell Cycle Phases ◽

And Control

Abstract INTRODUCTION: EPO regulates erythropoiesis by preventing apoptosis at the relatively late developmental stages of CFU-E and proerythroblasts. Cells in these EPO-dependent stages are actively dividing, but after several divisions they enter a G0 state from which they enucleate. In vivo these erythroid progenitor cells associate physically with macrophages in the bone marrow, forming erythroblastic islands. Erythroblastic islands appear to be necessary for proper development of erythroblasts into erythrocytes, but our current knowledge about erythroid progenitor-macrophage interactions in the erythroblastic islands is limited. METHODS: Spleens of mice in the acute erythroblastic phase of Friend virus disease were used to reconstitute erythroblastic islands in a co-culture system that enabled study of interactions between macrophages and developmentally synchronized EPO-dependent erythroid progenitors. Proliferation and differentiation of these erythroid progenitors in macrophage co-cultures was compared to controls in which the same erythroid progenitors were cultured alone. Erythroblasts adherent to macrophages and non-adherent erythroblasts from co-cultures, as well as control erythroblasts cultured without macrophages were collected at 6, 20, 32, and 44 hrs after initial culture for cell counts, cytospin preparations for morphology, flow cytometry analyses for apoptosis (TUNEL), cell cycle phases, and expression of two surface molecules known to be expressed on differentiating erythroblasts, phosphatidylserine (PS) and α4 integrin. Experiments were also done with erythroblasts cultured in macrophage-conditioned media. RESULTS: Splenic erythroblasts cultured alone proliferated 4.6 ± 0.7 fold over 44 h, while erythroblasts co-cultured with splenic macrophages proliferated 14.2 ± 2 fold (n=12). Control erythroblasts had the same proliferation in macrophage-conditioned medium as they did in normal medium. In EPO dose-response experiments, percentages of apoptosis were the same among adherent and non-adherent co-cultured erythroblasts and control erythroblasts. Cytospin preparations revealed no differences in morphology among non-adherent and adherent erythroblasts in co-cultures and control erythroblasts. No differences were found in enucleation percentages, extruded nuclei, or reticulocyte formation at 44 h. Likewise no differences were found in percentages of apoptotic cells, distribution of cell cycle phases, or surface expressions of PS or α4 integrin during the 44 h of differentiation. CONCLUSIONS: Co-culture with macrophages in reconstituted erythroblastic islands dramatically increases the erythroblast proliferation, without affecting differentiation. The increase in proliferation is not due to decreased apoptosis, increased EPO responsiveness, or soluble factors released by the macrophages. Preservation of EPO-dependence during this expansion of erythroblasts mediated by direct interaction with macrophages indicates that erythropoietic regulation by EPO affects a larger population of erythroid progenitor cells in later stages of erythropoiesis and, thereby, accounts for relatively rapid increases or decreases in erythrocyte production following changes in EPO levels in vivo.

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Activity of RN-1, an LSD-1 Inhibitor, on Fetal Globin Expression in Sickle Mice and Sickle Erythroid Progenitors

Blood ◽

10.1182/blood.v126.23.961.961 ◽

2015 ◽

Vol 126 (23) ◽

pp. 961-961 ◽

Cited By ~ 1

Author(s):

Shuaiying Cui ◽

Jose Sangerman ◽

Seyed Mehdi Nouraie ◽

Yan Dai ◽

Oluwakemi Owoyemi ◽

...

Keyword(s):

Progenitor Cells ◽

Hemolytic Anemia ◽

Conflicts Of Interest ◽

Globin Gene ◽

Clinical Severity ◽

Globin Genes ◽

Erythroid Progenitors ◽

Irreversible Inhibitor ◽

Erythroid Progenitor ◽

Erythroid Progenitor Cells

Abstract Sickle cell disease (SCD) is the most common monogenic disorder, afflicting millions worldwide, and causing hemolytic anemia and chronic organ damage from vaso-occlusion. Fetal hemoglobin (HbF) is an endogenous type of hemoglobin present in all humans during development, which is normally suppressed in infancy. Biochemical and clinical studies have shown that increased synthesis of HbF inhibits sickle hemoglobin (HbS) polymerization and reduces clinical severity. Concerted efforts have been made to induce the synthesis of HbF in adult erythroid cells with chemical inducers of HbF and through disruption of transcription factors in repressor complexes. As wide variability in individual responses to drug candidates have been observed in clinical trials, consistently effective HbF inducers are highly desired. We previously identified that Lysine-specific histone demethylase 1 (LSD1) is involved in the regulation of the fetal γ-globin genes, and inhibition of LSD1 using either RNAi or by the momoamine oxidase inhibitor tranylcypromine (TC) in primary human erythroid progenitor cells induces HbF to therapeutic levels. However, TC treatment has potentially problematic side effects, and at high concentrations decreases adult b-globin mRNAs and impairs erythroid maturation. We have now investigated another LSD1 inhibitor, RN-1, which is a cell-permeable TC analog that acts as a potent, irreversible inhibitor of LSD1 with a lower IC50 than TC. We investigated in vivo effects of RN-1 on γ-globin gene expression and erythroid physiology in a transgenic mouse model of SCD which expresses human α- and sickle β-globin, and has many genetic, hematologic, and pathophysiological features found in SCD patients, including irreversibly sickled RBCs, hemolytic anemia, high reticulocyte counts, hepatosplenomegaly and organ pathology. We found a robust increase in human fetal γ-globin (15-fold) and murine embryonic εY- and βH1-globin mRNAs (36 and 54-fold) and 4-fold increases in human HbF in SCD mice following repeated RN-1 treatment (at 10 μg/g body weight) within 4 weeks. Further, irreversibly sickled RBCs were significantly reduced, and RBC lifespan increased markedly in RN-1-treated SCD mice, leading to significantly decrease pathophysiologic indicators (hemolysis, splenomegaly, and organ necrosis) compared to untreated SCD mice. To begin to evaluate potential effects of RN-1 on erythroid progenitor cells from patients with SCD, peripheral blood from 5 adult SCD patients was cultured with RN-1 (0.07 to 0.25 μM) in a 2-phase progenitor assay, with mRNA analyzed on day 12 and F-reticulocytes on day 13-14 of the erythroid differentiation phase. RN-1 treated progenitors demonstrated a mean 3.4-fold higher g-globin mRNA (p=0.04) and 5% higher absolute F-reticulocytes than were observed in untreated progenitors from the same subject, with responses occurring in 5/5 subjects' assays. These preclinical studies provide additional evidence that modulating LSD-1 activity is a promising approach to inducing HbF expression as a mechanism to reduce clinical severity of SCD. Disclaimer: "Research reported in this publication was supported by the NHLBI under Award Number P50HL118006. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health" R01 DK052962 10A1 R42-HL-110727 Disclosures No relevant conflicts of interest to declare.

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Different repopulation profile between erythroid and nonerythroid progenitor cells in genetically anemic W/Wv mice after bone marrow transplantation

Blood ◽

10.1182/blood.v74.5.1552.1552 ◽

1989 ◽

Vol 74 (5) ◽

pp. 1552-1556 ◽

Cited By ~ 15

Author(s):

T Nakano ◽

N Waki ◽

H Asai ◽

Y Kitamura

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

Progenitor Cells ◽

Marrow Transplantation ◽

Bone Marrow Cells ◽

Electrophoretic Pattern ◽

Erythroid Progenitors ◽

Erythroid Progenitor ◽

Erythroid Progenitor Cells ◽

Donor Type

Abstract Repopulation kinetics of erythrocytes and neutrophils and replacement of hematopoietic progenitors were studied in genetically anemic (WB x C57BL/6)F1-W/Wv (WBB6F1-W/Wv) hosts after bone marrow transplantation from C57BL/6-bgJ/bgJ or C57BL/6-bgJ/bgJ;Pgk-1a/Y mice. Electrophoretic pattern of hemoglobin was used as a marker of donor-type erythrocytes, giant granules of bgJ/bgJ mice as a marker of donor-type neutrophils, and A-type phosphoglycerate kinase-1 (PGK-1) as a marker of hematopoietic colonies produced by donor-derived progenitor cells. Repopulation of donor-type erythrocytes was significantly faster than that of donor-type neutrophils. Moreover, the extent of replacement was greater for erythroid progenitor cells than for nonerythroid progenitor cells. When nonirradiated WBB6F1-W/Wv mice with B-type PGK-1 received 10(5) bone marrow cells from C57BL/6-bgJ/bgJ;Pgk-1a donors, only approximately 20% replacement of erythroid progenitor cells gave rise to total reconstitution of erythrocytes. The present result suggests that normal multipotential stem cells may preferentially differentiate into erythroid lineage cells in anemic WBB6F1-W/Wv hosts and that normal erythroid progenitor cells may suppress the differentiation of erythroid progenitors of WBB6F1-W/Wv hosts.

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The small 11kDa nonstructural protein of human parvovirus B19 plays a key role in inducing apoptosis during B19 virus infection of primary erythroid progenitor cells

Blood ◽

10.1182/blood-2009-04-215756 ◽

2010 ◽

Vol 115 (5) ◽

pp. 1070-1080 ◽

Cited By ~ 58

Author(s):

Aaron Yun Chen ◽

Elizabeth Yan Zhang ◽

Wuxiang Guan ◽

Fang Cheng ◽

Steve Kleiboeker ◽

...

Keyword(s):

Progenitor Cells ◽

Ex Vivo ◽

Nonstructural Protein ◽

Parvovirus B19 ◽

Death Receptor ◽

Human Parvovirus B19 ◽

Nonstructural Proteins ◽

Erythroid Progenitors ◽

Erythroid Progenitor ◽

Erythroid Progenitor Cells

AbstractHuman parvovirus B19 (B19V) infection shows a strong erythroid tropism and drastically destroys erythroid progenitor cells, thus leading to most of the disease outcomes associated with B19V infection. In this study, we systematically examined the 3 B19V nonstructural proteins, 7.5kDa, 11kDa, and NS1, for their function in inducing apoptosis in transfection of primary ex vivo–expanded erythroid progenitor cells, in comparison with apoptosis induced during B19V infection. Our results show that 11kDa is a more significant inducer of apoptosis than NS1, whereas 7.5kDa does not induce apoptosis. Furthermore, we determined that caspase-10, an initiator caspase in death receptor signaling, is the most active caspase in apoptotic erythroid progenitors induced by 11kDa and NS1 as well as during B19V infection. More importantly, cytoplasm-localized 11kDa is expressed at least 100 times more than nucleus-localized NS1 at the protein level in primary erythroid progenitor cells infected with B19V; and inhibition of 11kDa expression using antisense oligos targeting specifically to the 11kDa-encoding mRNAs reduces apoptosis significantly during B19V infection of erythroid progenitor cells. Taken together, these results demonstrate that the 11kDa protein contributes to erythroid progenitor cell death during B19V infection.

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