ArticleProceedings of the National Academy of Sciences of the United States of America2011
Forced TR2/TR4 expression in sickle cell disease mice confers enhanced fetal hemoglobin synthesis and alleviated disease phenotypes.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 41 citations in OpenAlex.
- Orphan Nuclear Receptors TR2 and TR4 in Erythropoiesis: From Mechanisms to Therapies.Biomolecules · 2025Review
- Review
- Interleukin-1 receptor inhibition reduces stroke size in a murine model of sickle cell disease.Haematologica · 2021Article
- Article
- Article
- mTOR Inhibition improves anaemia and reduces organ damage in a murine model of sickle cell disease.British journal of haematology · 2016Article
- Original Research: Generation of non-deletional hereditary persistence of fetal hemoglobin β-globin locus yeast artificial chromosome transgenic mouse models: -175 Black HPFH and -195 Brazilian HPFH.Experimental biology and medicine (Maywood, N.J.) · 2016Article
- TR2/TR4 overexpression in a humanized sickle cell disease mouse model decreases RBC adhesion to VCAM-1.Blood cells, molecules & diseases · 2015Article
- Intestine-specific Disruption of Hypoxia-inducible Factor (HIF)-2α Improves Anemia in Sickle Cell Disease.The Journal of biological chemistry · 2015Article
- Genomic approaches to identifying targets for treating β hemoglobinopathies.BMC medical genomics · 2015Review
- Article
- Anemia: progress in molecular mechanisms and therapies.Nature medicine · 2015Review
- BCL11A enhancer haplotypes and fetal hemoglobin in sickle cell anemia.Blood cells, molecules & diseases · 2015Article
- Article
- Recent trends in the gene therapy of β-thalassemia.Journal of blood medicine · 2015Review
- Epigenetic regulation of fetal globin gene expression in adult erythroid cells.Translational research : the journal of laboratory and clinical medicine · 2015Review
- Melanoma tumor growth is accelerated in a mouse model of sickle cell disease.Experimental hematology & oncology · 2015Article
- Fetal globin gene repressors as drug targets for molecular therapies to treat the β-globinopathies.Molecular and cellular biology · 2014Review
- Human fetal globin gene expression is regulated by LYAR.Nucleic acids research · 2014Article
- Minireview: Pathophysiological roles of the TR4 nuclear receptor: lessons learned from mice lacking TR4.Molecular endocrinology (Baltimore, Md.) · 2014Article
Corrections and comments
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Authors and funding
15 authors at 4 institutions in 2 countries.
Funding
Abstract
Sickle cell disease (SCD) is a hematologic disorder caused by a missense mutation in the adult β-globin gene. Higher fetal hemoglobin (HbF) levels in red blood cells of SCD patients have been shown to improve morbidity and mortality. We previously found that nuclear receptors TR2 and TR4 repress expression of the human embryonic ε-globin and fetal γ-globin genes in definitive erythroid cells. Because forced expression of TR2/TR4 in murine adult erythroid cells paradoxically enhanced fetal γ-globin gene expression in transgenic mice, we wished to determine if forced TR2/TR4 expression in a SCD model mouse would result in elevated HbF synthesis and thereby alleviate the disease phenotype. In a "humanized" sickle cell model mouse, forced TR2/TR4 expression increased HbF abundance from 7.6% of total hemoglobin to 18.6%, accompanied by increased hematocrit from 23% to 34% and reticulocyte reduction from 61% to 18%, indicating a significant reduction in hemolysis. Moreover, forced TR2/TR4 expression reduced hepatosplenomegaly and liver parenchymal necrosis and inflammation in SCD mice, indicating alleviation of usual pathophysiological characteristics. This article shows that genetic manipulation of nonglobin proteins, or transcription factors regulating globin gene expression, can ameliorate the disease phenotype in a SCD model animal. This proof-of-concept study demonstrates that modulating TR2/TR4 activity in SCD patients may be a promising therapeutic approach to induce persistent HbF accumulation and for treatment of the disease.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.