Gamma-Globin Gene Expression in Adult Human Erythroblasts Is Associated with Concurrent Changes in the Nuclear Protein Levels of at Least Seven Transcription Factors.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1866-1866
Author(s):  
Orapan Sripichai ◽  
Y. Terry Lee ◽  
Toshihiko Tanno ◽  
Seung-Jae Noh ◽  
Colleen Byrnes ◽  
...  
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Transcription Factors ◽  
Nuclear Protein ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Binding Motif ◽  
Gamma Globin ◽  
Protein Levels ◽  
Globin Gene Expression

Abstract Alterations of globin-gene cluster expression mediated through cytokine signal transduction have been previously established. In adult erythroblasts, ex vivo combinatorial signaling from cytokines such as erythropoietin (EPO), stem cell factor (SCF), and transforming growth factor-beta (TGF-B) causes a robust reactivation of fetal hemoglobin. To determine if cytokine-activated expression of fetal hemoglobin significantly alters the transcript and protein abundance of nuclear transcription factors, profiling studies of transcription factor expression were performed. Primary CD34+ cells were cultured as donor-matched pairs using cytokine combinations that produced low vs. high levels of gamma-globin mRNA and fetal hemoglobin (Bhanu et al. Blood, 2005). To identify candidate genes, total RNA from 15 separate healthy volunteer donors was collected and combined into 5 pools. The pooled RNA was labeled and hybridized to Affymetrix HG-U133 Plus 2.0 GeneChips. Informatics strategies were aimed toward identifying differential expression of those transcription factors with binding motif on any of the 10 human globin gene promoter regions (553 transcription factors; 115 binding motif families), versus all transcription factors demonstrating robust expression with changes of at least 3-fold. Combining both strategies, 11 candidate transcription factors were identified (BCL11A, CBFB, EGR-1, ELK-1, HHEX, ID2, MAFF, MNDA, SOX-6, TCF3, and THRB). RNA-based descriptions of gene activity do not necessarily reflect changes in protein levels; therefore, Western analyses were performed. GATA-1 was utilized as a control, since no significant change in GATA-1 mRNA was detected by expression array profiling. Nuclear protein extracts were obtained from 3 additional donors’ CD34+ cells cultured under conditions of low vs. high gamma-globin mRNA synthesis (1.6E+06 ± 3.8E+05 and 1.5E+07 ± 6.3E+06 copies/ng total RNA, respectively). Western blot analysis revealed reproducible and robust differences in protein expression levels for 7 of the 11 candidate transcription factors (EGR-1, ELK-1, HHEX, ID2, MAFF, MNDA, and SOX-6). Two other candidates were expressed below the protein detection limit. GATA-1 and the remaining 2 candidates demonstrated no change in the nuclear protein levels. Among the group with confirmed changes in gene expression, ELK-1 and EGR-1 are downstream targets of the MAP kinase signal transduction cascade. MAFF, ID2, and SOX-6 are known regulators of globin gene expression. The differential expression of HHEX and MNDA warrants further investigation. These data demonstrate that cytokine signal transduction causes changes in the intranuclear levels of at least 7 transcription factors concurrently with activation of gamma-globin gene expression.

scholarly journals Fetal hemoglobin in sickle cell anemia: relation to regulatory sequences cis to the beta-globin gene. Multicenter Study of Hydroxyurea

Blood ◽  
1996 ◽  
Vol 87 (4) ◽  
pp. 1604-1611 ◽  
Author(s):  
ZH Lu ◽  
MH Steinberg
Keyword(s):  
Gene Expression ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Regulatory Sequences ◽  
Beta Globin ◽  
Beta Globin Gene ◽  
Gamma Globin ◽  
Globin Gene Expression

Very different fetal hemoglobin levels among adult sickle cell anemia patients suggest genetic modulation of gamma-globin gene expression. In sickle cell anemia, different fetal hemoglobin levels are associated with distinct beta-globin gene haplotypes. Haplotype may be a marker for linked DNA that modulates gamma-globin gene expression. From 295 individuals with sickle cell anemia, we chose for detailed studies 53 patients who had the highest or the lowest fetal hemoglobin levels and 7 patients whose fetal hemoglobin levels were atypical of their haplotype. In these individuals, we examined portions of the beta- globin gene locus control region hypersensitive sites two and three, an (AT)x(T)y repeat 5′ to the beta-globin gene, a 4-bp deletion 5 to the A gamma T gene, promoters of both gamma-globin genes, 5′ flanking region of the G gamma-globin gene, and A gamma-globin gene IVS-II. Of the regions we studied all polymorphisms were always haplotype-linked and no additional mutations were present. This suggested that variations in these areas are uncommon mechanisms of fetal hemoglobin modulation in sickle cell anemia. Whereas unexamined cis-acting sequences may regulate gamma-globin gene transcription, trans-acting factors may play a more important role.

Novel Hybrids of Hydroxyurea and Thalidomide Based Pharmacophores Induce Fetal Hemoglobin and Block Monocyte Activation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2673-2673
Author(s):  
Carolina Lanaro ◽  
Carla Franco-Penteado ◽  
Jean Leandro Santos ◽  
Marlene Wade ◽  
Shobha Yerigenahally ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mononuclear Cells ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Cytokine Release ◽  
Gamma Globin ◽  
Tnf Α ◽  
Activated Monocytes ◽  
Humidified Air ◽  
Globin Gene Expression

Abstract Abstract 2673 Introduction: Fetal hemoglobin induction is an effective strategy for the treatment of sickle cell disease (SCD). In addition, targeting systemic inflammation, which consists of activated and injured vascular endothelium, elevated pro-inflammatory cytokines, and activated WBC, promises to reduce vaso-occlusion and disease severity. We therefore aimed to develop novel compounds that combine potent HbF-inducing and anti-inflammatory activities with the goal to improve treatment outcomes. In principle, our rational drug design used molecular hybridization to synthesize three compounds (Lapdesf 1, 2, 3) that link Hydroxyurea's nitric oxide-donating nitrate ester subunit and thalidomide's phthalimide ring with three different intermolecular spacers. Hydroxyurea is to date the only FDA approved drug for the treatment of adult patients with SCD that induces HbF and reduces clinical complications. The release of nitric oxide by HU is an important mechanism of its HbF-inducing properties. On the other hand, thalidomide and its recently developed IMiD derivatives potently inhibit cytokine release from activated monocytes and suppress adhesion molecule expression on vascular endothelium. These properties are critically linked to the phthalimide ring in the thalidomide molecule. The aim of this study was to evaluate the effects of three novel hybrid compounds Lapdesf 1 (2-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]ethyl nitrate), Lapdesf 2 (4-[1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl]-N-hydroxybenzenesulfonamide), and Lapdesf 3 (3-[1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl]benzyl nitrate) on γ-globin gene expression and cytokine release from activated monocytes. Methods: 1. Gamma-globin gene expression. Human K562 cells were maintained in DMEM with 10% FBS, Pen/Strep, in humidified air (5% CO2, 37°C). Cells (1×107cells/100mL) were incubated with compounds at different concentrations (5, 30, 60, and 100μM) for 24, 48, 72 and 96h. Gamma-globin gene expression was analyzed by qRT-PCR and quantified using the Gnorm program. Results were expressed as arbitrary units. 2. Monocyte stimulation. Animals: Adult knockout-transgenic sickle cell mice were anesthetized with Ketamine/Xylazine and blood collected by intracardiac puncture. Mononuclear cells were purified from peripheral blood using Ficoll gradient separation. Mononuclear cells were placed in plastic dishes with DMEM with 10% calf serum and incubated for 2 h in humidified air (5% CO2, at 37°C). Purity of monocytes was > 90% as determined by May-Giemsa staining. Lapdesf 1, 2, and 3 were added to the monocytes cultures at different concentrations (100μM, 300μM and 600μM) 30 minutes before LPS (1 μg/ml). After 20 h incubation supernatants were collected and stored at −80°C. Cytokines were determined by ELISA. Results: 1. Gamma-globin gene expression. Lapdesf 1 and 2 were equipotent and demonstrated inverse dose-response relationships achieving the highest levels of γ-globin induction at 5 and 30 μM; in contrast, Lapdesf 2 achieved maximal γ-globin induction as early as 24h after treatment, whereas Lapdesf 1 required 72h of incubation (Lapdesf 2 [24h; 5 μM]: 1.48±0.06 AU; control 0.78±0.1 AU; P<0.05; Lapdesf 1 [72h; 5 μM] 1.78±0.5 AU; control 0.64±0.26; P<0.05). Testing of Lapdesf 3 is currently underway. 2. Monocyte stimulation. Monocytes from sickle mice produced significantly higher levels of TNF-α (1.9 fold), IL-6 (3.48 fold), IL-8 (1.95 fold) and IL-1β (3.42 fold) after LPS stimulation compared to hemizygous controls (P<0.05). Lapdesf 1 and 3 (300 μM) significantly suppressed cytokine production compared to vehicle in LPS-stimulated sickle monocytes and were more potent inhibitors than dexamethasone (Lapdesf 1; Lapdesf 3; Dex: TNF-α : −14.71 fold; −4.64 fold; −4.44 fold; n ≥5; P<0.001; IL-6: −35.68 fold; −12.46 fold, −6.13 fold; n ≥5; P<0.001; IL-8: −7.83 fold; −3.10 fold; −2.55 fold; n ≥5; P<0.001; IL-1β: −14.34 fold; −5.26 fold; −8.9 fold; n ≥5; P<0.01). Lapdesf 2 (300 μM) failed to block cytokine release. Conclusions: These results provide proof-of-concept that our hybrid compounds utilizing critical hydroxyurea and thalidomide based pharmacophores are capable of potent HbF stimulation and anti-inflammatory activities. Testing of our lead compound Lapdesf 1in a preclinical mouse model of SCD is currently underway to evaluate its efficacy in the treatment of this hemoglobinopathy. Disclosures: No relevant conflicts of interest to declare.

Targeting a Novel Epigenetic Silencing Mechanism to Efficiently Upregulate Fetal Globin Gene Expression

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 352-352
Author(s):  
Fabiana Perna ◽  
Ly P. Vu ◽  
Maria Themeli ◽  
Ruben Hoya-Arias ◽  
Xinyang Zhao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chromatin Structure ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Erythroid Differentiation ◽  
Ips Cells ◽  
Gamma Globin ◽  
Cd34 Cells ◽  
Hes Cells ◽  
Globin Gene Expression

Abstract Abstract 352 L3MBTL1 is a Polycomb group protein, commonly deleted in patients with myeloid disorders associated with the 20q- chromosomal abnormality. After crystallizing the MBT repeat domain, we demonstrated that L3MBTL1 compacts chromatin by binding mono- and di-methylated lysine residues in histones H1 (H1K26) and H4 (H4K20), ultimately leading to gene repression. Despite its role in affecting the chromatin structure, the role of L3MBTL1 in hematopoiesis has remained largely unknown. We recently demonstrated that lack of L3MBTL1 accelerates the erythroid differentiation of human hematopoietic stem cells and here we reveal that L3MBTL1 represses the expression of the fetal gamma globin gene. We lentivirally expressed shRNAs targeting L3MBTL1 in human cord blood (CB) CD34+ cells and in K562 erythroleukemia cells, and consistently observed upregulation of gamma globin gene expression, while beta globin gene expression decreased. Remarkably, we observed similar findings in human embryonic stem (hES) cells, where knock-down of L3MBTL1 triggered a BMP4-like spontaneous differentiation. Given the potential impact of therapeutically increasing fetal hemoglobin expression in patients with hemoglobinopathies, we targeted L3MBTL1 in induced pluripotent stem (iPS) cells derived from patients with β-thalassemia. The gene expression profile of L3MBTL1-KD normal and thalassemic iPS cells indicated clear activation of fetal hemoglobin (HbF) expression, activation of BMP4 signaling and upregulation of specific smad5 target genes (e.g. EKLF, HHEX, ID2/3). We generated and utilized a model of “stress erythropoiesis” in L3MBTL1 KO mice and observed in vivo BMP4-mediated expansion of spleen immature erythroid progenitors, as indicated by increased spleen weight and splenic BFU-E colonies in KO mice compared to controls. We also examined K562 cells, human CB CD34+ cells and hES cells, using chromatin immunoprecipitation assays, and found that L3MBTL1 directly associates with the human β-globin locus, occupying discrete regions within the human β-globin cluster. Furthermore, L3MBTL1 colocalized with H4K20me within the Locus Control Region (LCR), a primary attachment site for chromatin modifiers. We observed clearance of L3MBTL1 and its associated histone marks (H4K20me1/2) from the LCR upon treatment with hemin, erythropoietin or TGFβ, three agents that potently induce erythroid differentiation. This suggests that this polycomb repressor complex responds to cytokine signaling. In summary, we have identified a novel epigenetic regulatory mechanism to control fetal globin gene expression; the Polycomb protein L3MBTL1 regulates BMP4 signaling and the chromatin structure of globin genes. Targeting this regulatory system represents a means to efficiently increase HbF in a human model of β-thalassemia (i.e. with the use of patient-derived iPS cells) and to potentially ameliorate hematological and clinical symptoms of patients with red cell disorders. Disclosures: No relevant conflicts of interest to declare.

High Throughput Screen To Identify Small Molecules That Differentially Regulate Expression of the Globin Genes.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3632-3632
Author(s):  
Benjamin L. Ebert ◽  
Raymond Mak ◽  
Jennifer L. Pretz ◽  
David Peck ◽  
Stephen Haggerty ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Throughput ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Beta Thalassemia ◽  
Globin Genes ◽  
Beta Globin ◽  
Diversity Oriented Synthesis ◽  
Gamma Globin ◽  
Globin Gene Expression

Abstract Several lines of evidence indicate that the pharmacological activation of fetal hemoglobin is an effective therapy for sickle cell anemia and beta thalassemia, but novel treatments for these diseases are needed. We developed and validated a high throughput assay to detect differential regulation of the globin genes and utilized this assay in a small molecule screen to identify novel compounds that increase the relative expression of gamma globin. In our assay, transcripts for the alpha, beta, delta, epsilon, gamma, theta, and zeta globin genes are amplified by multiplexed ligation-mediated PCR. Labeled amplicons are captured on different fluorescent microspheres using molecular barcodes, and the relative abundance of labeled amplicons is detected by high speed flow cytometry. To recapitulate the activity of compounds in the bone marrow of patients as accurately as possible, the screen was performed using primary human erythroid progenitor cells cultured in vitro. The assay was adapted to 384-well format with robotic liquid handling. In validation studies, the assay detected the expected increases in globin gene expression during erythroid differentiation, increased gamma globin expression in umbilical cord blood progenitor cells, and increased gamma globin expression in cells treated with known inducers of fetal hemoglobin including hydroxyurea and sodium butyrate. We screened a library of 1040 known bioactive compounds, 75% of which are FDA approved drugs, and a library of 600 compounds produced by diversity oriented synthesis that have been shown to inhibit histone deacetylase (HDAC) activity. In the screen, we rediscovered previously identified globin gene regulators, further validating our globin assay. For example, corticosteroids, known activators of fetal hemoglobin, increased the relative expression of gamma globin. Thyroid hormone specifically increased expression of delta globin, consistent with clinical observations that hemoglobin A2 levels are increased in hyperthyroidism and decreased in hypothyroidism. We identified ten novel compounds from the diversity oriented synthesis library that powerfully induce expression of the gamma globin gene relative to beta globin. Moreover, HDAC inhibition reversed the ontogeny of globin gene expression, coordinately increasing expression of fetal and embryonic relative to the adult globin genes. Relative to beta globin gene expression, gamma and epsilon globin were induced while delta globin was unaffected by HDAC inhibitors; relative to alpha globin expression, zeta globin was increased and theta globin was unaffected. The identification of compounds that differentially regulate globin gene expression may provide lead compounds for the development of novel therapies for sickle cell disease and beta thalassemia and may help elucidate the molecular events underlying switching of the globin genes during normal development.

scholarly journals Epigenetic Insights and Potential Modifiers as Therapeutic Targets in β–Thalassemia

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 755
Author(s):  
Nur Atikah Zakaria ◽  
Md Asiful Islam ◽  
Wan Zaidah Abdullah ◽  
Rosnah Bahar ◽  
Abdul Aziz Mohamed Yusoff ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Presentation ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Dna Hypomethylation ◽  
Considerable Research ◽  
Non Coding Rna ◽  
Hbf Level ◽  
Long Non Coding Rna ◽  
Globin Gene Expression

Thalassemia, an inherited quantitative globin disorder, consists of two types, α– and β–thalassemia. β–thalassemia is a heterogeneous disease that can be asymptomatic, mild, or even severe. Considerable research has focused on investigating its underlying etiology. These studies found that DNA hypomethylation in the β–globin gene cluster is significantly related to fetal hemoglobin (HbF) elevation. Histone modification reactivates γ-globin gene expression in adults and increases β–globin expression. Down-regulation of γ–globin suppressor genes, i.e., BCL11A, KLF1, HBG-XMN1, HBS1L-MYB, and SOX6, elevates the HbF level. β–thalassemia severity is predictable through FLT1, ARG2, NOS2A, and MAP3K5 gene expression. NOS2A and MAP3K5 may predict the β–thalassemia patient’s response to hydroxyurea, a HbF-inducing drug. The transcription factors NRF2 and BACH1 work with antioxidant enzymes, i.e., PRDX1, PRDX2, TRX1, and SOD1, to protect erythrocytes from oxidative damage, thus increasing their lifespan. A single β–thalassemia-causing mutation can result in different phenotypes, and these are predictable by IGSF4 and LARP2 methylation as well as long non-coding RNA expression levels. Finally, the coinheritance of β–thalassemia with α–thalassemia ameliorates the β–thalassemia clinical presentation. In conclusion, the management of β–thalassemia is currently limited to genetic and epigenetic approaches, and numerous factors should be further explored in the future.

scholarly journals EHMT1 and EHMT2 inhibition induces fetal hemoglobin expression

Blood ◽  
2015 ◽  
Vol 126 (16) ◽  
pp. 1930-1939 ◽  
Author(s):  
Aline Renneville ◽  
Peter Van Galen ◽  
Matthew C. Canver ◽  
Marie McConkey ◽  
John M. Krill-Burger ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Locus ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Erythroid Cells ◽  
Adult Human ◽  
Key Points ◽  
Globin Gene Expression

Key Points EHMT1/2 inhibition increases human γ-globin and HbF expression, as well as mouse embryonic β-globin gene expression. EHMT1/2 inhibition decreases H3K9Me2 and increases H3K9Ac at the γ-globin gene locus in adult human erythroid cells.

scholarly journals Expression of the affected A gamma globin gene associated with Greek nondeletion hereditary persistence of fetal hemoglobin.

1987 ◽  
Vol 7 (8) ◽  
pp. 2999-3003 ◽  
Author(s):  
C J Stoeckert ◽  
J E Metherall ◽  
M Yamakawa ◽  
J M Eisenstadt ◽  
S M Weissman ◽  
...  
Keyword(s):  
Transcription Initiation ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Mutant Gene ◽  
Retroviral Vector ◽  
Base Substitution ◽  
Gamma Globin ◽  
Erythroleukemia Cell ◽  
Hereditary Persistence ◽  
Globin Gene Expression

The overexpressed A gamma globin gene in the Greek type of nondeletion hereditary persistence of fetal hemoglobin has a unique single-base substitution located at position -117 relative to the site of transcription initiation. This gene and its normal counterpart were transferred into cultured cell lines by using a retroviral vector. The only difference in expression between the transferred normal and mutant gamma genes was observed in the human erythroleukemia cell line KMOE after exposure of the cells to cytosine arabinoside, a condition that resulted in an adult pattern of endogenous globin gene expression by the cells and was associated with increased expression of the mutant gene.

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

Blood ◽  
2009 ◽  
Vol 114 (11) ◽  
pp. 2299-2306 ◽  
Author(s):  
Orapan Sripichai ◽  
Christine M. Kiefer ◽  
Natarajan V. Bhanu ◽  
Toshihiko Tanno ◽  
Seung-Jae Noh ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Protein Expression ◽  
Histone Modification ◽  
Globin Gene ◽  
Expression Patterns ◽  
Fetal Hemoglobin ◽  
Transcriptome Profiling ◽  
Globin Genes

Abstract 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, and adult globin transcript and protein expression patterns were determined for comparison. Chromatin immunoprecipitation assays revealed RNA polymerase II occupancy and histone tail modifications consistent with transcriptional activation only in the high-HbF culture condition. Transcriptome profiling studies demonstrated reproducible changes in expression of nuclear transcription factors associated with high HbF. Among the 13 genes that demonstrated differential transcript levels, 8 demonstrated nuclear protein expression levels that were significantly changed by cytokine signal transduction. Five of the 8 genes are recognized regulators of erythropoiesis or globin genes (MAFF, ID2, HHEX, SOX6, and EGR1). Thus, cytokine-mediated signal transduction in adult erythroid cells causes significant changes in the pattern of globin gene and protein expression that are associated with distinct histone modifications as well as nuclear reprogramming of erythroid transcription factors.

scholarly journals Association ofXmnI Polymorphism and Hemoglobin E Haplotypes on Postnatal Gamma Globin Gene Expression in Homozygous Hemoglobin E

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Supachai Ekwattanakit ◽  
Yuwarat Monteerarat ◽  
Suchada Riolueang ◽  
Kalaya Tachavanich ◽  
Vip Viprakasit
Keyword(s):  
Gene Expression ◽  
Globin Gene ◽  
Laboratory Data ◽  
Regulatory Sequences ◽  
Chromosome 11 ◽  
Hemoglobin E ◽  
Association Analyses ◽  
Gamma Globin ◽  
Hb E ◽  
Globin Gene Expression

Background and Objectives. To explore the role ofcis-regulatory sequences within theβglobin gene cluster at chromosome 11 on humanγglobin gene expression related to Hb E allele, we analyze baseline hematological data and Hb F values together withβglobin haplotypes in homozygous Hb E.Patients and Methods. 80 individuals with molecularly confirmed homozygous Hb E were analyzed for theβglobin haplotypes andXmnI polymorphism using PCR-RFLPs. 74 individuals with complete laboratory data were further studied for association analyses.Results. Eight differentβglobin haplotypes were found linked to Hb E alleles; three major haplotypes were (a) (III), (b) (V), and (c) (IV) accounting for 94% of Hb E chromosomes. A new haplotype (Th-1) was identified and most likely converted from the major ones. The majority of individuals had Hb F < 5%; only 10.8% of homozygous Hb E had high Hb F (average 10.5%, range 5.8–14.3%). No association was found on a specific haplotype orXmnI in these individuals with high Hb F, measured by alkaline denaturation. Conclusion. The cis-regulation ofγglobin gene expression might not be apparent under a milder condition with lesser globin imbalance such as homozygous Hb E.

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