A sustained and pancellular reversal of gamma-globin gene silencing in adult human erythroid precursor cells

Bhanu, Natarajan V.; Trice, Tiffany A.; Lee, Y. Terry; Gantt, Nicole M.; O'Neal, Patricia; Schwartz, Joseph D.; Noël, Pierre; Miller, Jeffery L.

doi:10.1182/blood-2004-04-1599

Cited by 36 publications

(47 citation statements)

References 28 publications

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“…15 The combination of stem cell factor and transforming growth factor-beta signal transduction produces a marked increase in ␥-globin transcript and protein expression. Because cytokine signaling may affect the expression of the additional globin genes, the study began by examining the expression patterns of each gene.…”

Section: Changes In Globin Gene and Protein Expression Patterns In Rementioning

confidence: 99%

“…Primary CD34 ϩ cells from 15 healthy donors (collected after National Institutes of Health Institutional Review Board approval and informed consent obtained in accordance with the Declaration of Helsinki) were cultured for 14 days as described previously, 15 with low-HbF culture conditions; EPO alone (4 U/mL; Amgen), versus high-HbF culture conditions; EPO, stem cell factor (50 ng/mL; R&D Systems), and transforming growth factor-␤ (1.25 ng/mL; R&D Systems). Eagle minimum essential medium was utilized containing 30% fetal bovine serum, 1% deionized bovine serum albumin, 40 mM glutamine, 1 U/mL penicillinstreptomycin, 100 M ␤-mercaptoethanol, 1 M dexamethasone, and 0.3 mg/mL holotransferrin.…”

Section: Primary Erythroblast Culturesmentioning

confidence: 99%

“…In particular, the combination of erythropoietin (EPO), stem cell factor, and transforming growth factor-␤ was shown to increase HbF expression in adult human erythroblasts to levels more than 20% without dramatic changes in the viability, growth, or differentiation of the cells. 15 These cytokines act via phosphorylation cascades that originate at the cell surface. However, the nuclear mechanisms responsible for the cytokine-induced increase in ␥-globin transcript are not understood.…”

Section: Introductionmentioning

confidence: 99%

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Cytokine-mediated increases in fetal hemoglobin are associated with globin gene histone modification and transcription factor reprogramming

Sripichai

Kiefer

Bhanu

et al. 2009

Blood

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Therapeutic regulation of globin genes is a primary goal of translational research aimed toward hemoglobinopathies. Signal transduction was used to identify chromatin modifications and transcription factor expression patterns that are associated with globin gene regulation. Histone modification and transcriptome profiling were performed using adult primary CD34 ؉ cells cultured with cytokine combinations that produced low versus high levels of gamma-globin mRNA and fetal hemoglobin (HbF). Embryonic, fetal,

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Section: Changes In Globin Gene and Protein Expression Patterns In Rementioning

confidence: 99%

Section: Primary Erythroblast Culturesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cytokine-mediated increases in fetal hemoglobin are associated with globin gene histone modification and transcription factor reprogramming

Sripichai

Kiefer

Bhanu

et al. 2009

Blood

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“…Thus, despite their opposite effects on erythroid cell growth, SCF and TGF-β had synergistic effects with respect to HbF synthesis [217]. In erythroid cultures supplemented with Epo+SCF+TGF-β, about a 40% level of HbF synthesis was observed, with a pancellular distribution of HbF in erythroid cells [217]. The analysis of the effects of glucocorticoids on HbF synthesis in cooperation with SCF was prompted from studies showing that corticosteroids, such as dexamethasone, cooperate with Epo and SCF to enhance and sustain the proliferation of erythroid progenitors [218].…”

Section: Stem Cell Factormentioning

confidence: 95%

“…Two molecules, transforming growth factor-β (TGF-β) and corticosteroids, potentiate the effect of SCF on HbF synthesis. Thus, despite their opposite effects on erythroid cell growth, SCF and TGF-β had synergistic effects with respect to HbF synthesis [217]. In erythroid cultures supplemented with Epo+SCF+TGF-β, about a 40% level of HbF synthesis was observed, with a pancellular distribution of HbF in erythroid cells [217].…”

Section: Stem Cell Factormentioning

confidence: 99%

Fetal hemoglobin chemical inducers for treatment of hemoglobinopathies

Testa¹

2008

Ann Hematol

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Sustained and full fetal hemoglobin production after failure of bone marrow transplant in a patient homozygous for beta 0‐thalassemia: A clinical remission despite genetic disease and transplant rejection

et al. 2009

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An adult patient affected by b 0 -thalassemia major underwent allogeneic bone marrow transplant (BMT) from a matched related donor. Forty days after transplant, allogeneic engraftment failure and autologous b 0 -thalassemic bone marrow recovery were documented. Red blood cell transfusions were required until 118 days post-transplant. Thereafter, the haemoglobin (Hb) levels stabilized over 11.8 gr/dl throughout the ongoing 34-month follow-up, abolishing the need for transfusion support. The Hb electrophoresis showed 100% Hb Fetal (HbF). This unexplained case suggests full HbF production may occur in an adult patient with b 0 -thalassemia major.Homozygous b-thalassemia is a severe disorder caused by inheritance of two b-thalassemia alleles. The gene mutations produce absent or insufficient synthesis of b-globin chains leading to excess a-globin chain accumulation and precipitation in early erythroid cells [1]. Concurrent genetic factors (hereditary persistence of fetal hemoglobin(HbF), a-gene mutations, and db-thalassemia determinants) are known to modify the globin chain imbalance [1,2].To date, the only cure for thalassemia major is stem cell transplantation [3]. Here, we report an atypical case of sustained and full HbF production after graft failure in an adult b 0 -thalassemic patient.On September 2005, an 18-year-old patient affected by b 0 -thalassemia major was referred to our center for bone marrow transplant (BMT) from an HLA identical sibling.The thalassemia Major diagnosis was evident by 2 years of age when the blood transfusion therapy was started and regularly administered every 2-3 weeks. After splenectomy, performed when the patient was 6 years old, the transfusion requirement was reduced to one red blood cell unit every 2-3 months. Such behavior was maintained during the following years without any transfusion-free period. The iron-chelation therapy was never administered.At the time of presentation to our Institution, the patient presented typical thalassemic facies and hepatomegaly (over 4 cm below the ribs). The complete blood counts showed: low Hb level (9.7 g/dl), low red blood cell count (3.59 3 10 12 /l), a mean corpuscular volume of 82 fl, a mild increase of reticulocyte count (4.07%), increased white cell count (3.901 3 10 12 /l), abundant circulating nucleated red cells (80% of total nucleated cells), and an elevated platelet count (803 3 10 9 /l). The bone marrow exhibited marked hypercellularity.The Hb profile showed predominantly HbF (73.6%), and the genetic analysis detected a double mutation in the b-globin locus: the homozygous mutation IVS-I-1 of the b-globin gene and the homozygous mutation for T variant at position 2158 upstream of the Gg-globin gene. High-performance liquid chromatography (HPLC) analyses detected the lack of b-chain synthesis (b 0%) and 2.47% of the a/non a imbalance.Chronic hepatitis C was documented by a HCV-RNA test. Liver biopsy showed mild fibrosis (1/6 degree) and marked iron overload ([3/4] histological score). The liver iron concentration was marked el...

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A sustained and pancellular reversal of gamma-globin gene silencing in adult human erythroid precursor cells

Cited by 36 publications

References 28 publications

Cytokine-mediated increases in fetal hemoglobin are associated with globin gene histone modification and transcription factor reprogramming

Cytokine-mediated increases in fetal hemoglobin are associated with globin gene histone modification and transcription factor reprogramming

Fetal hemoglobin chemical inducers for treatment of hemoglobinopathies

Sustained and full fetal hemoglobin production after failure of bone marrow transplant in a patient homozygous for beta 0‐thalassemia: A clinical remission despite genetic disease and transplant rejection

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