Rb Plays an Essential Role in Erythroid Differentiation through Inhibition of Apoptosis Mediated by NFKB.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 308-308
Author(s):  
Sahoko Matsuoka ◽  
Atsushi Hirao ◽  
Fumio Arai ◽  
Keiyo Takubo ◽  
Kana Miyamoto ◽  
...  
Keyword(s):  
Essential Role ◽  
Molecular Mechanisms ◽  
Fetal Liver ◽  
Erythroid Differentiation ◽  
Severe Anemia ◽  
Cell Surface Markers ◽  
Hematopoietic Progenitors ◽  
Hematopoietic Stem ◽  
Rb Gene ◽  
Terminal Erythroid Differentiation

Abstract Inactivation of the retinoblastoma (Rb) gene results in embryonic lethality due to severe anemia and increased nucleated erythrocytes by day14. However, molecular mechanisms of the function of Rb in erythroid differentiation have been unclear. Recent studies have suggested that Rb has both intrinsic and extrinsic roles on erythroid differentiation. Using Rb-deficient (Rb−/−) embryos(E12), we showed that Rb regulates terminal erythroid differentiation through inhibition of apoptosis mediated by NFKB. Enucleation of erythroblasts was impaired in semisolid culture of Rb−/− hematopoietic progenitors in fetal liver. The lethally-irradiated recipient mice transplanted with Rb−/− hematopoietic stem cells (HSCs) showed severe anemia with splenomegaly, whereas the number of leukocytes and platelets were normal. In Rb−/− recipient mice, the nucleated erythrocytes and reticulocytes were significantly increased in the peripheral blood. We analyzed cell surface markers for erythroid lineage (TER119 and CD71) in the enlarged spleen. A block of erythroid differentiation at the early erythroblast stage (TER119high CD71high), accompanied with increased apoptosis, was observed in the recipient mice with Rb−/− HSCs. We speculated that the defect in the erythroid differentiation of Rb−/− HSCs might be caused by inappropriate cell death. Thus, we examined expression of apoptosis-related genes in early erythroblasts (CD71high Ter119high) and observed decrease of Bcl-XL expression. To clarify the function of Bcl-XL, we introduced exogenous cDNA of mouse Bcl-XL with GFP (Bcl-XL ires GFP) or GFP alone as control into HSCs and then transplanted them to lethally irradiated mice. From the point of CD71 and Ter119 expression pattern in GFP positive cells, Rb−/− erythoblasts still showed the block in differentiation. In contrast, overexpression of Bcl-XL in Rb−/− erythoblasts inhibited inappropriated apoptosis and restore the differentiation capacity. Further, we found that inactivation of NFKB, but not STAT5 in Rb−/− erythroblasts. Treatment of NFKB inhibitor suppressed erythroid differentiation, accompanied by enucleation, and also inhibited upregulation of Bcl-XL. These data demonstrates that Rb is essential for erythroid differentiation through inhibition of apoptosis mediated by NFKB.

Rb Regulates Erythroid Differentiation through Bcl-XL-Dependent Anti-Apoptotic Effect.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1261-1261
Author(s):  
Sahoko Matsuoka ◽  
Atsushi Hirao ◽  
Fumio Arai ◽  
Keisuke Ito ◽  
Keiyo Takubo ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Fetal Liver ◽  
Annexin V ◽  
Erythroid Differentiation ◽  
Severe Anemia ◽  
Rt Pcr ◽  
Hematopoietic Stem ◽  
Apoptotic Effect ◽  
Rb Gene ◽  
Terminal Erythroid Differentiation

Abstract Inactivation of the retinoblastoma (Rb) gene results in embryonic lethality due to severe anemia and increased nucleated erythrocytes by day E14.5. However, molecular mechanisms of the function of Rb in erythroid differentiation have been unclear. Recent studies have suggested that Rb has both intrinsic and extrinsic roles on erythroid differentiation. Here we showed that Rb regulates terminal erythroid differentiation through inhibition of apoptosis. Enucleation of erythroblasts was impaired in semisolid culture of Rb−/− hematopoietic progenitors in fetal liver. The lethally-irradiated recipient mice transplanted with Rb−/− hematopoietic stem cells (HSCs) showed severe anemia (Hgb 8.2±1.47 g/dl versus WT :12.0±1.22 g/dl) with splenomegaly, whereas the number of leukocytes and platelets were normal. In Rb−/− recipient mice, the nucleated erythrocytes and reticulocytes were significantly increased in the peripheral blood. We analyzed cell surface markers for erythroid lineage (TER119 and CD71) in the enlarged spleen. A block of erythroid differentiation at the early erythroblast stage, accompanied with increased apoptosis, was observed in the recipient mice with Rb−/− HSCs. We speculated that the defect in the erythroid differentiation of Rb−/− HSCs might be caused by inappropriate cell death. Thus, we examined expression profiling for apoptosis-related genes in early erythroblasts (CD71highTer119high) by RT-PCR. Interestingly, the dramatic decrease of Bcl-XL expression was detected in the erythroblasts, whereas other Bcl-2 family members including Bcl-2 and Bax were unchanged. To clarify the function of Bcl-XL, we introduced exogenous cDNA of mouse Bcl-XL with GFP (Bcl-XL ires GFP) or GFP alone as control into HSCs and then transplanted them to lethally irradiated mice. From the point of CD71 and Ter119 expression pattern in GFP positive cells, Rb−/− erythoblasts still showed the block in differentiation. In contrast, a ratio of late erythroblasts in Bcl-XL expressing cells was higher than that in GFP control cells in Rb−/− recipient mice and a number of annexin V positive cells were much reduced in the mice transplanted with Bcl-XL expressing cells, indicating that overexpression of Bcl-XL inhibited inappropriated apoptosis and restored the differentiation. These data demonstrates that Rb regulates erythroid differentiation through Bcl-XL-dependent anti-apoptotic effect.

scholarly journals Deciphering Molecular Control of VEGFR2 Regulation in Hematopoietic Progenitors: GATA1-Mediated Repression of VEGFR2 Promotes Optimum Erythropoiesis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1172-1172
Author(s):  
Avishek Ganguly ◽  
Omar S. Aljitawi ◽  
Soumen Paul
Keyword(s):  
Stem Cells ◽  
Molecular Mechanisms ◽  
Fetal Liver ◽  
Embryonic Stem ◽  
Erythroid Differentiation ◽  
Hematopoietic Progenitors ◽  
Erythroid Progenitors ◽  
Hematopoietic Stem ◽  
Molecular Control ◽  
Endothelial Development

Abstract VEGFR2 (also known as Flk1) is expressed in hemetopoietic precursors and is essential for both hematopoietic and vascular development. Interestingly, development of differentiated hematopoietic cell from hematopoietic stem cells (HSCs) is associated with VEGFR2 repression, whereas VEGFR2 expression is maintained throughout endothelial development. This differential regulation of VEGFR2 has been implicated as a key step to successfully branch out hematopoietic vs. endothelial development. However, molecular mechanisms that regulate transcriptionally active vs. repressive Vegfr2 chromatin domains in hematopoietic stem/progenitor cells (HSPCs) vs. differentiated hematopoietic cells are incompletely understood. Here, we report that transcription factor GATA1, a master-regulator of erythroid differentiation, is essential to repress VEGFR2 expression in erythroid progenitors. Genetic complementation analysis demonstrated that VEGFR2 expression in maintained in GATA1-null erythroid progenitors and rescue of GATA1-function induces VEGFR2 repression. Mechanistic studies in primary hematopoietic progenitors from mouse fetal liver and differentiating mouse embryonic stem cells (ESCs) identified a repressor element at the (-)88 kb region of the Vegfr2 locus from which GATA1 represses Vegfr2 transcription in erythroid progenitors. Furthermore, CRISPR/Cas9-mediated deletion of the Vegfr2(-)88 kb region results in reduced erythroid differentiation during fetal liver hematopoiesis. These results indicate that GATA1-mediated repression of VEGFR2 could be a determinant of optimum erythropoiesis. Disclosures No relevant conflicts of interest to declare.

Essential Function of PDGF-B Signaling In the Placental Microenvironment In Protecting Hematopoietic Progenitors From Erythroid Differentiation.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1559-1559
Author(s):  
Akanksha Chhabra ◽  
Andrew J Lechner ◽  
Asha Acharya ◽  
Masaya Ueno ◽  
Ben Van Handel ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Fetal Liver ◽  
Hematopoietic Cells ◽  
Erythroid Differentiation ◽  
Postnatal Life ◽  
Hematopoietic Progenitors ◽  
Hematopoietic Stem ◽  
Hematopoietic Organ ◽  
Fetal Hematopoiesis ◽  
Definitive Erythropoiesis

Abstract Abstract 1559 The goals of hematopoiesis during embryogenesis are two-fold, to rapidly produce red blood cells to support the survival and development of the embryo, and to establish a pool of undifferentiated hematopoietic stem cells (HSC) for postnatal life. These goals are achieved by segregation of fetal hematopoiesis in multiple waves that are executed in distinct anatomical sites and microenvironmental niches. However, the microenvironmental cues that promote “stemness” vs. differentiation remain poorly understood. The placenta is a recently discovered hematopoietic organ that supports HSC generation and expansion without promoting their differentiation. The placental HSC pool is thought to reside in the placental labyrinth, which is comprised of an intricate vascular network surrounded by trophoblasts. So far, it has been unknown how a disruption of the integrity of the placental vascular labyrinth affects fetal hematopoiesis. The structure of the placental labyrinth is compromised in embryos that lack components of PDGF-B signaling. PDGF-B-/- and PDGF-Rβ-/- (receptor for PDGF-B) embryos display dilation of fetal blood vessels and reduction of trophoblast cells in the placental labyrinth. Our studies revealed that loss of PDGF-B signaling alters the unique placental hematopoietic microenvironment, resulting in active erythropoiesis in the placenta. The unexpected erythropoiesis in the placenta exhibited the same hallmarks of normal definitive erythropoiesis observed in the fetal liver as confirmed by flow cytometry for erythroid markers, morphological analysis and association of erythroblasts with macrophages. Interestingly, deletion of PDGF-Rβ in hematopoietic cells by using a Tie2-Cre strain did not induce the differentiation of placental hematopoietic progenitors into erythroid cells, implying that the ectopic definitive erythropoiesis results from the lack of PDGF-B signaling in the placental microenvironment rather than in the hematopoietic cells themselves. Our studies revealed that the erythroid differentiation in placentas of PDGF-B-/- embryos was induced by marked upregulation of Epo in placental trophoblasts. Strikingly, lentiviral overexpression of Epo specifically in the placental trophoblasts was sufficient to convert the placenta into an ectopic erythropoietic organ. These data reveal a critical function of PDGF-B signaling in protecting the integrity of the placental microenvironment that is required for preventing hematopoietic progenitors from differentiation during their residence in the placenta. Furthermore, these studies highlight the placenta as a versatile hematopoietic organ that supports HSC development during normal pregnancy but can be recruited as a site for definitive erythropoiesis during pathological conditions. Disclosures: No relevant conflicts of interest to declare.

The Hox cofactor and proto-oncogene Pbx1 is required for maintenance of definitive hematopoiesis in the fetal liver

Blood ◽  
2001 ◽  
Vol 98 (3) ◽  
pp. 618-626 ◽  
Author(s):  
Jorge F. DiMartino ◽  
Licia Selleri ◽  
David Traver ◽  
Meri T. Firpo ◽  
Joon Rhee ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Fetal Liver ◽  
Chromosomal Translocations ◽  
Severe Anemia ◽  
Hematopoietic Progenitors ◽  
Homeodomain Proteins ◽  
Acute Leukemias ◽  
Hematopoietic Stem ◽  
Definitive Hematopoiesis

Abstract Pbx1 is the product of a proto-oncogene originally discovered at the site of chromosomal translocations in acute leukemias. It binds DNA as a complex with a broad subset of homeodomain proteins, but its contributions to hematopoiesis have not been established. This paper reports that Pbx1 is expressed in hematopoietic progenitors during murine embryonic development and that its absence results in severe anemia and embryonic lethality at embryonic day 15 (E15) or E16. Definitive myeloerythroid lineages are present inPbx1−/−fetal livers, but the total numbers of colony-forming cells are substantially reduced. Fetal liver hypoplasia reflects quantitative as well as qualitative defects in the most primitive multilineage progenitors and their lineage-restricted progeny. Hematopoietic stem cells from Pbx1−/−embryos have reduced colony-forming activity and are unable to establish multilineage hematopoiesis in competitive reconstitution experiments. Common myeloid progenitors (CMPs), the earliest known myeloerythroid-restricted progenitors, are markedly depleted inPbx1−/−embryos at E14 and display clonogenic defects in erythroid colony formation. Comparative cell-cycle indexes suggest that these defects result largely from insufficient proliferation. Megakaryocyte- and erythrocyte-committed progenitors are also reduced in number and show decreased erythroid colony-forming potential. Taken together, these data indicate that Pbx1 is essential for the function of hematopoietic progenitors with erythropoietic potential and that its loss creates a proliferative constriction at the level of the CMP. Thus, Pbx1 is required for the maintenance, but not the initiation, of definitive hematopoiesis and contributes to the mitotic amplifications of progenitor subsets through which mature erythrocytes are generated.

scholarly journals First blood: the endothelial origins of hematopoietic progenitors

Angiogenesis ◽  
2021 ◽  
Author(s):  
Giovanni Canu ◽  
Christiana Ruhrberg
Keyword(s):  
Stem Cells ◽  
Molecular Mechanisms ◽  
Vascular Endothelial Cells ◽  
Fetal Liver ◽  
Cell Types ◽  
Yolk Sac ◽  
Vascular Endothelial ◽  
Hematopoietic Stem ◽  
Close Proximity ◽  
Clinical Interest

AbstractHematopoiesis in vertebrate embryos occurs in temporally and spatially overlapping waves in close proximity to blood vascular endothelial cells. Initially, yolk sac hematopoiesis produces primitive erythrocytes, megakaryocytes, and macrophages. Thereafter, sequential waves of definitive hematopoiesis arise from yolk sac and intraembryonic hemogenic endothelia through an endothelial-to-hematopoietic transition (EHT). During EHT, the endothelial and hematopoietic transcriptional programs are tightly co-regulated to orchestrate a shift in cell identity. In the yolk sac, EHT generates erythro-myeloid progenitors, which upon migration to the liver differentiate into fetal blood cells, including erythrocytes and tissue-resident macrophages. In the dorsal aorta, EHT produces hematopoietic stem cells, which engraft the fetal liver and then the bone marrow to sustain adult hematopoiesis. Recent studies have defined the relationship between the developing vascular and hematopoietic systems in animal models, including molecular mechanisms that drive the hemato-endothelial transcription program for EHT. Moreover, human pluripotent stem cells have enabled modeling of fetal human hematopoiesis and have begun to generate cell types of clinical interest for regenerative medicine.

Impairment of human terminal erythroid differentiation by histone deacetylase 5 deficiency

Blood ◽  
2021 ◽  
Author(s):  
Yaomei Wang ◽  
Wei Li ◽  
Vince Schulz ◽  
Huizhi Zhao ◽  
Xiaoli Qu ◽  
...  
Keyword(s):  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Chromatin Condensation ◽  
Erythroid Differentiation ◽  
Chromatin Accessibility ◽  
Erythroid Cell ◽  
Global Changes ◽  
Human Cd34 ◽  
Wide Range ◽  
Terminal Erythroid Differentiation

Histone deacetylases (HDACs) are a group of enzymes catalyzing the removal of acetyl groups from histone and non-histone proteins. HDACs have been shown to play diverse functions in a wide range of biological processes. However, their roles in mammalian erythropoiesis remain to be fully defined. We show here that of the eleven classic HDAC family members, six of them (HDAC 1,2,3 and HDAC 5,6,7) are expressed in human erythroid cells with HDAC5 most significantly up regulated during terminal erythroid differentiation. Knockdown of HDAC5 by either shRNA or siRNA in human CD34+ cells followed by erythroid cell culture led to increased apoptosis, decreased chromatin condensation, and impaired enucleation of erythroblasts. Biochemical analyses revealed that HDAC5 deficiency resulted in activation of p53 in association with increased acetylation of p53. Furthermore, while acetylation of histone 4 (H4) is decreased during normal terminal erythroid differentiation, HDAC5 deficiency led to increased acetylation of H4 (K12) in late stage erythroblasts. This increased acetylation was accompanied by decreased chromatin condensation, implying a role for H4 (K12) deacetylation in chromatin condensation. ATAC-seq and RNA-seq analyses revealed that HDAC5 knockdown leads to increased chromatin accessibility genome wide and global changes in gene expression. Moreover, pharmacological inhibition of HDAC5 by the inhibitor LMK235 also led to increased H4 acetylation, impaired chromatin condensation and enucleation. Taken together, our findings have uncovered previously unrecognized roles and molecular mechanisms of action for HDAC5 in human erythropoiesis. These results may provide insights into understanding the anemia associated with HDAC inhibitor treatment.

scholarly journals Definitive-like erythroid cells derived from human embryonic stem cells coexpress high levels of embryonic and fetal globins with little or no adult globin

Blood ◽  
2006 ◽  
Vol 108 (5) ◽  
pp. 1515-1523 ◽  
Author(s):  
Kai-Hsin Chang ◽  
Angelique M. Nelson ◽  
Hua Cao ◽  
Linlin Wang ◽  
Betty Nakamoto ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Human Embryonic Stem Cells ◽  
Molecular Mechanisms ◽  
Embryoid Body ◽  
Fetal Liver ◽  
Embryonic Stem ◽  
Erythroid Differentiation ◽  
Erythroid Cells ◽  
Promising Tool

Human embryonic stem cells are a promising tool to study events associated with the earliest ontogenetic stages of hematopoiesis. We describe the generation of erythroid cells from hES (H1) by subsequent processing of cells present at early and late stages of embryoid body (EB) differentiation. Kinetics of hematopoietic marker emergence suggest that CD45+ hematopoiesis peaks at late D14EB differentiation stages, although low-level CD45- erythroid differentiation can be seen before that stage. By morphologic criteria, hES-derived erythroid cells were of definitive type, but these cells both at mRNA and protein levels coexpressed high levels of embryonic (ϵ) and fetal (γ) globins, with little or no adult globin (β). This globin expression pattern was not altered by the presence or absence of fetal bovine serum, vascular endothelial growth factor, Flt3-L, or coculture with OP-9 during erythroid differentiation and was not culture time dependent. The coexpression of both embryonic and fetal globins by definitive-type erythroid cells does not faithfully mimic either yolk sac embryonic or their fetal liver counterparts. Nevertheless, the high frequency of erythroid cells coexpressing embryonic and fetal globin generated from embryonic stem cells can serve as an invaluable tool to further explore molecular mechanisms.

scholarly journals Decreased PGC1β expression results in disrupted human erythroid differentiation, impaired hemoglobinization and cell cycle exit

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Taha Sen ◽  
Jun Chen ◽  
Sofie Singbrant
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Mitochondrial Function ◽  
Iron Homeostasis ◽  
Erythroid Differentiation ◽  
Refractory Anemia ◽  
Cell Cycle Exit ◽  
Erythroid Progenitors ◽  
Hematopoietic Stem ◽  
Terminal Erythroid Differentiation

AbstractProduction of red blood cells relies on proper mitochondrial function, both for their increased energy demands during differentiation and for proper heme and iron homeostasis. Mutations in genes regulating mitochondrial function have been reported in patients with anemia, yet their pathophysiological role often remains unclear. PGC1β is a critical coactivator of mitochondrial biogenesis, with increased expression during terminal erythroid differentiation. The role of PGC1β has however mainly been studied in skeletal muscle, adipose and hepatic tissues, and its function in erythropoiesis remains largely unknown. Here we show that perturbed PGC1β expression in human hematopoietic stem/progenitor cells from both bone marrow and cord blood results in impaired formation of early erythroid progenitors and delayed terminal erythroid differentiation in vitro, with accumulations of polychromatic erythroblasts, similar to MDS-related refractory anemia. Reduced levels of PGC1β resulted in deregulated expression of iron, heme and globin related genes in polychromatic erythroblasts, and reduced hemoglobin content in the more mature bone marrow derived reticulocytes. Furthermore, PGC1β knock-down resulted in disturbed cell cycle exit with accumulation of erythroblasts in S-phase and enhanced expression of G1-S regulating genes, with smaller reticulocytes as a result. Taken together, we demonstrate that PGC1β is directly involved in production of hemoglobin and regulation of G1-S transition and is ultimately required for proper terminal erythroid differentiation.

Expression of CD41 marks the initiation of definitive hematopoiesis in the mouse embryo

Blood ◽  
2003 ◽  
Vol 101 (2) ◽  
pp. 508-516 ◽  
Author(s):  
Hanna K. A. Mikkola ◽  
Yuko Fujiwara ◽  
Thorsten M. Schlaeger ◽  
David Traver ◽  
Stuart H. Orkin
Keyword(s):  
Endothelial Cells ◽  
Mouse Embryo ◽  
Fetal Liver ◽  
Stem Cell Differentiation ◽  
Yolk Sac ◽  
Embryoid Bodies ◽  
Embryonic Stem Cell Differentiation ◽  
Hematopoietic Progenitors ◽  
Hematopoietic Stem ◽  
Definitive Hematopoiesis

Murine hematopoietic stem cells (HSCs) originate from mesoderm in a process that requires the transcription factor SCL/Tal1. To define steps in the commitment to blood cell fate, we compared wild-type and SCL−/− embryonic stem cell differentiation in vitro and identified CD41 (GpIIb) as the earliest surface marker missing from SCL−/− embryoid bodies (EBs). Culture of fluorescence-activated cell sorter (FACS) purified cells from EBs showed that definitive hematopoietic progenitors were highly enriched in the CD41+ fraction, whereas endothelial cells developed from CD41− cells. In the mouse embryo, expression of CD41 was detected in yolk sac blood islands and in fetal liver. In yolk sac and EBs, the panhematopoietic marker CD45 appeared in a subpopulation of CD41+ cells. However, multilineage hematopoietic colonies developed not only from CD45+CD41+ cells but also from CD45−CD41+ cells, suggesting that CD41 rather than CD45 marks the definitive culture colony-forming unit (CFU-C) at the embryonic stage. In contrast, fetal liver CFU-C was CD45+, and only a subfraction expressed CD41, demonstrating down-regulation of CD41 by the fetal liver stage. In yolk sac and EBs, CD41 was coexpressed with embryonic HSC markers c-kit and CD34. Sorting for CD41 and c-kit expression resulted in enrichment of definitive hematopoietic progenitors. Furthermore, the CD41+c-kit+ population was missing from runx1/AML1−/− EBs that lack definitive hematopoiesis. These results suggest that the expression of CD41, a candidate target gene of SCL/Tal1, and c-kit define the divergence of definitive hematopoiesis from endothelial cells during development. Although CD41 is commonly referred to as megakaryocyte–platelet integrin in adult hematopoiesis, these results implicate a wider role for CD41 during murine ontogeny.

The Role of K-ras Signaling in Erythropoiesis In Vivo.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3136-3136
Author(s):  
Jing Zhang ◽  
Yangang Liu ◽  
Caroline Beard ◽  
Rudolf Jaenisch ◽  
Tyler Jacks ◽  
...  
Keyword(s):  
Fetal Liver ◽  
Erythroid Differentiation ◽  
Liver Cells ◽  
Ras Signaling ◽  
Erythroid Progenitors ◽  
Akt Activation ◽  
Fetal Liver Cells ◽  
Terminal Erythroid Differentiation

Abstract K-ras plays an important role in hematopoiesis. K-ras-deficient mouse embryos die around E12-E13 with severe anemia. In humans, oncogenic mutations in K-ras gene are identified in ~30% of patients with acute myeloid leukemia. We used mouse primary erythroid progenitors as a model system to study the role of K-ras signaling in vivo. Both Epo- and stem cell factor (SCF) - dependent Akt activation are greatly reduced in K-ras-/- fetal liver cells, whereas other cytokine- induced pathways, including Stat5 and p44/p42 MAP kinase, are activated normally. The reduced Akt activation in erythroid progenitors per se leads to delayed erythroid differentiation. Our data identify K-ras as the major regulator for cytokine-dependent Akt activation, which is important for erythroid differentiation in vivo. Overexpression of oncogenic Ras in primary fetal erythroid progenitors led to their continual proliferation and a block in terminal erythroid differentiation. Similarly, we found that primary fetal liver cells expressing oncogenic K-ras from its endogenous locus undergo abnormal proliferation and terminal erythroid differentiation is partially blocked. We are currently investigating the signal transduction pathways activated by this oncogenic K-ras that underlies these cellular phenotypes.

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