Induction of human fetal hemoglobin via the NRF2 antioxidant response signaling pathway

Macari, Elizabeth R.; Lowrey, Christopher H.

doi:10.1182/blood-2010-10-314096

Cited by 71 publications

(72 citation statements)

References 48 publications

(57 reference statements)

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“…KU812 cells are a human leukemia cell line expressing both fetal γ-globin and adult β-globin genes shown to increase expression of HbF in response to known β-Hb switching agents, including heme and sodium butyrate (36). Our studies confirmed that Nrf2 activation leads to occupancy of the ARE consensus sites in the γ-globin gene promoters, in agreement with published data with K562 erythroleukemia cells and erythroid progenitors generated from normal peripheral CD34 + cells treated with the Nrf2 activator tert-butylhydroquinone (tBHQ) (25). HbF induction, heme detoxification, and vascular protection were studied in vivo using Townes SCD mice.…”

Section: Discussionsupporting

confidence: 90%

“…DMF is a small molecule of which the primary mechanism of action is to increase the accumulation of Nrf2, a transcription factor that is involved in activation of downstream genes that are vital in protecting cells from injurious oxidative free radicals. Recently published reports have demonstrated the importance of the Nrf2 pathway in activating HbF in human erythroid cells differentiated from BM-derived CD34 + progenitor cells (25). In this study, we observed HbF induction by DMF in SCD donor PBMC-derived erythroid progenitors.…”

Section: Discussionsupporting

confidence: 68%

“…The proximal promoters of the HBG1 and HBG2 genes are conserved (24) and contain consensus ARE sites. Drug-mediated Nrf2 activation leads to induction of HbF at both transcript and protein levels in cultured CD34 + stem cell-derived erythroid cells (25).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Dimethyl fumarate increases fetal hemoglobin, provides heme detoxification, and corrects anemia in sickle cell disease

Krishnamoorthy¹,

Pace²,

Gupta³

et al. 2017

JCI Insight

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 68%

See 1 more Smart Citation

Dimethyl fumarate increases fetal hemoglobin, provides heme detoxification, and corrects anemia in sickle cell disease

Krishnamoorthy¹,

Pace²,

Gupta³

et al. 2017

JCI Insight

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“…54 A variety of additional factors have been related to hemoglobin switching, including COUP-TF, FOP (Friend of PRMT1), Ikaros, miR-15 and 16, MBD2, NF-E4, NRF2, and TR2/TR4. 53,[55][56][57][58][59][60][61] The previously mentioned studies implicate specific transcription factors in the developmental control of the globin genes. Each of these factors acts within larger multiprotein complexes with chromatin-modifying activity.…”

Section: State Of the Fieldmentioning

confidence: 97%

Reawakening fetal hemoglobin: prospects for new therapies for the β-globin disorders

Bauer

Kamran

Orkin

2012

Blood

163

144

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IntroductionHemoglobinopathies are among the most common inherited recessive diseases. 1 Globin gene mutations occurred numerous times during human history and have been selected to high frequencies in malarial endemic regions. Although many of these globin mutations in the heterozygous state afford modest protection against malaria, the coinheritance of 2 mutant ␤-globin alleles (in homozygous or compound heterozygous combination) produces the common ␤-globin disorders. Sickle cell disease (SCD) and the ␤-thalassemias are chronic diseases with considerable morbidity and mortality. In low-income countries, most affected individuals die in early childhood. Nearly 300 000 infants are estimated born with SCD each year (the majority in Africa), and another 40 000 severely affected with ␤-thalassemia. 2 In the United States alone, the annual medical costs for the approximately 75 000 individuals with SCD are estimated at more than $1 billion. 3 Although genetic screening and prenatal diagnosis have reduced the incidence of ␤-thalassemia in selected countries, such as Sardinia and Cyprus, ␤-thalassemia remains common in many areas of Asia and the Middle East with limited resources for treatment. Children with ␤-globin disorders are at particular risk of life-threatening infections. As childhood infectious diseases are brought under better control in the developing world, the ␤-globin disorders will undoubtedly take on intensified public health significance. Given anticipated population growth, the worldwide prevalence of these diseases is expected to rise dramatically over the next century. 4 Since the initial hematologic descriptions of SCD and ␤-thalassemia by Herrick and Cooley, respectively, in the early 20th century, studies of the hemoglobinopathies have been at the forefront of human genetics and molecular biology. Sickle cell disease, distinguished by its unique hemoglobin structure because of the characteristic glutamate-to-valine substitution of ␤ S , was heralded as the first "molecular disease." 5page543 The subsequent demonstration of globin chain imbalance as the pathophysiologic underpinning of the thalassemias presaged the molecular biology era in which various thalassemia mutations were dissected, illuminating fundamental aspects of gene regulation. 6 Fetal hemoglobinTwo gene clusters encode the various globins-the ␣ cluster on chromosome 16 contains the embryonic gene, and adult ␣1 and ␣2 genes, and the ␤ cluster on chromosome 11 the embryonic ⑀, the fetal G ␥ and A ␥, and adult ␦ and ␤ genes (Figure 1). 7 During early embryonic development, erythropoiesis is yolk-sac-derived, transitioning to the fetal liver midway through the first trimester. Approaching the time of birth, the bone marrow becomes the dominant site of erythropoiesis. Two accompanying switches occur in the expression of genes from the ␤-globin cluster-a switch from embryonic-to-fetal globins early in gestation, and then from fetal-to-adult globins around the time of birth. Thus HbF (␣ 2 ␥ 2 ) constitutes the major hemoglobin during...

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“…[132][133][134][135] Recently, NRF2 inducers have attracted attention in the globin field due to their ability to activate g-globin transcription and HbF production in human erythroid cells (Table 2). Macari and Lowrey 109 reported that the known NRF2 inducers tert-butylhydroquione (tBHQ), curcumin and 2-dithiole-3-thione, induce g-globin and NQO1 transcription in K562 cells; moreover, increased NRF2 binding to the ARE region was observed in the promoters of these genes. In later studies, Lowrey and colleagues showed combining tBHQ and simvastatin (an FDA-approved drug used for cardiovascular disease), induced g-globin and NQO1 transcription in an additive manner; 32 simvastatin also induced HbF production in human primary erythroid progenitors (Table 2).…”

Section: Hbf Induction By Nrf2 Activatorsmentioning

confidence: 99%

Cell signaling pathways involved in drug-mediated fetal hemoglobin induction: Strategies to treat sickle cell disease

Pace

Liu

et al. 2015

Exp Biol Med (Maywood)

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The developmental regulation of globin gene expression has shaped research efforts to establish therapeutic modalities for individuals affected with sickle cell disease and b-thalassemia. Fetal hemoglobin has been shown to block sickle hemoglobin S polymerization to improve symptoms of sickle cell disease; moreover, fetal hemoglobin functions to replace inadequate hemoglobin A synthesis in b-thalassemia thus serving as an effective therapeutic target. In the perinatal period, fetal hemoglobin is synthesized at high levels followed by a decline to adult levels by one year of age. It is known that naturally occurring mutations in the g-globin gene promoters and distant cis-acting transcription factors produce persistent fetal hemoglobin synthesis after birth to ameliorate clinical symptoms. Major repressor proteins that silence g-globin during development have been targeted for gene therapy in b-hemoglobinopathies patients. In parallel effort, several classes of pharmacological agents that induce fetal hemoglobin expression through molecular and cell signaling mechanisms have been identified. Herein, we reviewed the progress made in the discovery of signaling molecules targeted by pharmacologic agents that enhance g-globin expression and have the potential for future drug development to treat the b-hemoglobinopathies.

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Induction of human fetal hemoglobin via the NRF2 antioxidant response signaling pathway

Cited by 71 publications

References 48 publications

Dimethyl fumarate increases fetal hemoglobin, provides heme detoxification, and corrects anemia in sickle cell disease

Dimethyl fumarate increases fetal hemoglobin, provides heme detoxification, and corrects anemia in sickle cell disease

Reawakening fetal hemoglobin: prospects for new therapies for the β-globin disorders

Cell signaling pathways involved in drug-mediated fetal hemoglobin induction: Strategies to treat sickle cell disease

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