Regulation of human fetal hemoglobin: new players, new complexities

Bank, Arthur

doi:10.1182/blood-2005-05-2113

Cited by 194 publications

(155 citation statements)

References 126 publications

(246 reference statements)

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“…[10][11][12][13] The cause of this variability is poorly understood. 11,12,29,30 HbF concentration in blood is determined by interactions among chromosome remodeling activities, transcription factors, genes modulating erythropoiesis, genetic elements linked to the b-globin gene cluster, the kinetics of erythroid cell differentiation and differential red cell survival (for reviews see Bank 31 and Stamatoyannopoulos 32 ). This complex regulatory environment provides ample opportunity for genetic modulation of HbF production.…”

Section: Discussionmentioning

confidence: 99%

Fetal hemoglobin in sickle cell anemia: genetic determinants of response to hydroxyurea

et al. 2007

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The increase in fetal hemoglobin (HbF) in response to hydroxyurea (HU) varies among patients with sickle cell anemia. Twenty-nine candidate genes within loci previously reported to be linked to HbF level (6q22.3-q23.2, 8q11-q12 and Xp22.2-p22.3), involved in metabolism of HU and related to erythroid progenitor proliferation were studied in 137 sickle cell anemia patients treated with HU. Three-hundred and twenty tagging single nucleotide polymorphisms (SNPs) for genotyping were selected based on HapMap data. Multiple linear regression and the nonlinear regression Random Forest method were used to investigate the association between SNPs and the change in HbF level after 2 years of treatment with HU. Both methods revealed that SNPs in genes within the 6q22.3-23.2 and 8q11-q12 linkage peaks, and also the ARG2, FLT1, HAO2 and NOS1 genes were associated with the HbF response to HU. Polymorphisms in genes regulating HbF expression, HU metabolism and erythroid progenitor proliferation might modulate the patient response to HU.

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Section: Discussionmentioning

confidence: 99%

Fetal hemoglobin in sickle cell anemia: genetic determinants of response to hydroxyurea

et al. 2007

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“…In the second step (days 10-13), cells were diluted at 5 ϫ 10 4 or 10 5 cells/mL (for CB or mPB, respectively) and cocultured on an adherent MS5 stromal layer in basal medium supplemented with erythropoietin. In the third step (days [13][14][15][16][17][18][19][20], cells were cultured on MS5 cells in basal medium without cytokine.…”

Section: Lentiviral Vectorsmentioning

confidence: 99%

“…[25][26][27] Fetal-to-adult switch needs interaction of transcription factors and chromatin remodeling proteins with the locus control region (LCR). 16,17,21,28 Analyses of transcription factors revealed the importance of erythropoiesis regulation at the transcriptional level. GATA1 is crucial for differentiation, expression of erythroid genes (such as ␤-globin, FOG1, EKLF, and NFE2), and for survival of erythroid cells.…”

Section: Introductionmentioning

confidence: 99%

“…The human ␤-globin locus contains different genes that are successively expressed during ontogeny. 16,20,21 ␥-globin genes are first expressed in fetal liver and cord blood (CB) erythropoiesis. 19,22 Shortly after birth, a switch between fetal and adult globins allows the expression of ␦-and ␤-globin genes, and the decrease of ␥-globin gene expression.…”

Section: Introductionmentioning

confidence: 99%

“…15 These studies show that Ikaros is necessary to the formation of the PYR complex, and to switching of murine and human globins. 16,17 The role of Ikaros in erythropoiesis is confirmed by another Ikaros mutation: Ikaros plastic mice have a single amino acid change in the third zinc finger of the N-terminal domain (ENU-induced nucleotide mutation), and die between embryonic day (E) 15.5 and E17.5 with severe anemia 18 ; numbers of erythroid progenitors (erythroid colony-forming units [CFUs-E] and erythroid blastforming units [BFUs-E]), normoblasts, and nonnucleated reticulocytes are reduced, which is due to a failure of normal erythroblast growth and differentiation.The earliest committed erythroid progenitor is the BFU-E, which then differentiates into CFUs-E. The more immature morphologically identifiable cells are proerythroblasts.…”

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confidence: 99%

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The role of Ikaros in human erythroid differentiation

Dijon

Bardin

Murati

et al. 2008

Blood

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Ikaros-a factor that positively or negatively controls gene transcription-is active in murine adult erythroid cells, and involved in fetal to adult globin switching. Mice with Ikaros mutations have defects in erythropoiesis and anemia. In this paper, we have studied the role of Ikaros in human erythroid development for the first time. Using a gene-transfer strategy, we expressed Ikaros 6 (Ik6)-a known dominant-negative protein that interferes with normal Ikaros activity-in cord blood or apheresis CD34 ؉ cells that were induced to differentiate along the erythroid pathway. Lentivirally induced Ik6-forced expression resulted in increased cell death, decreased cell proliferation, and decreased expression of erythroid-specific genes, including GATA1 and fetal and adult globins. In contrast, we observed the maintenance of a residual myeloid population that can be detected in this culture system, with a relative increase of myeloid gene expression, including PU1. IntroductionThe transcription factor Ikaros (also known as LyF-1) was first described to interact with Cd3␦ and TdT promoters in murine thymocyte cells. 1,2 Its sequence is highly conserved between mice and humans, [3][4][5] and its expression is high in the developing and adult hematopoietic systems. 1,6 Ikaros proteins are characterized by the presence of 2 Krüppel-like zinc finger domains. The N-terminal domain is involved in DNA binding, 2,7 while the C-terminal domain is required for homo-or heterodimerization with family members and is composed of 2 zinc fingers. 8 The Ikaros gene contains 7 translated exons and encodes 9 isoforms by means of alternative splicing that alters expression of exons 3 to 6. 2,7 In these different proteins, the number of N-terminal zinc fingers varies from 0 to 4; this combination determines DNA binding affinity. At least 3 zinc fingers in this domain are necessary to efficiently bind to DNA. Ik1, Ik2, Ik3, and IKX are considered as functional isoforms. However, Ik4 can only bind DNA on palindromic sequences. 7 Ik5, Ik6, Ik7, and Ik8 are considered dominantnegative (DN) isoforms because of their capacity to bind other isoforms and their inefficiency to bind DNA. 8 Gene-targeting studies evidenced the fundamental role of Ikaros in hematopoiesis, in particular in T and B lymphocytes, natural killer (NK) and dendritic cells, and stem cells. [9][10][11][12] In addition, analysis of Ikaros L/L mice (insertion of the ␤-Gal gene in exon-2 of the Ikaros gene) revealed that Ikaros is expressed at low levels in a majority of Ter-119 ϩ erythroid cells. 10 Other studies of Ikaros DN (deletion of exon 7) and null (deletion of dimerization domain) mice show that Ikaros is important for erythroid differentiation. 13 These mice display a decrease of erythroid precursor numbers, and a drop in hematocrit levels 2 to 3 weeks after birth. In MEL (murine erythroleukemia) cells, Ikaros is associated with the chromatin remodelling PYR complex which binds to an intergenic domain between the ␥-globin and ␤-globin genes, and facilitates the switch be...

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Gene Therapy for Severe Haemoglobin Disorders

Villamizar

Chambers

Wilber

2014

Encyclopedia of Life Sciences

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Sickle cell disease (SCD) and β‐thalassaemia result from inherited mutations that cause structural abnormality or deficient synthesis of adult haemoglobin. Palliative therapies improve the quality/duration of life for many, but side effects result from long‐term use. Bone marrow transplantation can be curative, but is limited to individuals with a matched donor. Thus, gene delivery into the patient's haematopoietic stem cells is a desirable therapy. Lentiviral vectors encoding for erythroid‐specific expression of either γ‐ or β‐globin genes have been developed for this purpose. These vectors have been used to cure SCD and β‐thalassaemia in mouse models with positive results emerging from clinical trials. Concurrently, innovative strategies intending to reactivate endogenous γ‐globin expression or correct β‐globin mutations at the genome level are showing promise for the future. Ultimately, clinical utility of all these approaches depend on safety and efficacy so that a cure can be consistently achieved. Key Concepts: Sickle cell disease (SCD) and β‐thalassaemia are the most common single gene disorders, and a worldwide health concern. The switch from foetal to adult haemoglobin production after birth marks the onset of disease. Haematopoietic stem cell transplant is curative, but available to only a limited number of patients making gene therapy a highly desirable alternative. Lentiviral vectors made possible the delivery of complex, erythroid‐specific globin expression cassettes into haematopoietic stem cells. Mouse models of SCD and β‐thalassaemia have been cured with lentiviral vectors encoding for high‐level, erythroid specific expression of γ‐ and β‐globin genes. The first adult β‐thalassaemia major patient treated with a β‐globin lentiviral vector remains transfusion‐independent and in good health 6 years after therapy.

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Regulation of human fetal hemoglobin: new players, new complexities

Cited by 194 publications

References 126 publications

Fetal hemoglobin in sickle cell anemia: genetic determinants of response to hydroxyurea

Fetal hemoglobin in sickle cell anemia: genetic determinants of response to hydroxyurea

The role of Ikaros in human erythroid differentiation

Gene Therapy for Severe Haemoglobin Disorders

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