Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 46, Pages 18808-18813Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1104964108
Keywords
repression; NR2C1; NR2C2; beta-thalassemia; therapeutic target
Categories
Funding
- American Heart Association
- Cooley's Anemia Foundation
- National Institutes of Health [DK086956, HL24415]
- National Heart, Lung and Blood Institute/National Institutes of Health [K01 HL03011]
- The Robert Wood Johnson Foundation [RWJ-AMFDP 051891]
- Grants-in-Aid for Scientific Research [20678002] Funding Source: KAKEN
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Sickle cell disease (SCD) is a hematologic disorder caused by a missense mutation in the adult beta-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 epsilon-globin and fetal gamma-globin genes in definitive erythroid cells. Because forced expression of TR2/TR4 in murine adult erythroid cells paradoxically enhanced fetal gamma-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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