Forced TR2/TR4 expression in sickle cell disease mice confers enhanced fetal hemoglobin synthesis and alleviated disease phenotypes

Andrew D. Campbell, Shuaiying Cui, Lihong Shi, Rebekah Urbonya, Andrea Mathias, Kori Bradley, Kwaku O. Bonsu, Rhonda R. Douglas, Brittne Halford, Lindsay Schmidt, David Harro, Donald Giacherio, Keiji Tanimoto, Osamu Tanabe, James Douglas Engel

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32 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)18808-18813
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number46
DOIs
Publication statusPublished - 2011 Nov 15

Keywords

  • NR2C1
  • NR2C2
  • Repression
  • Therapeutic target
  • β-thalassemia

ASJC Scopus subject areas

  • General

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    Campbell, A. D., Cui, S., Shi, L., Urbonya, R., Mathias, A., Bradley, K., Bonsu, K. O., Douglas, R. R., Halford, B., Schmidt, L., Harro, D., Giacherio, D., Tanimoto, K., Tanabe, O., & Engel, J. D. (2011). Forced TR2/TR4 expression in sickle cell disease mice confers enhanced fetal hemoglobin synthesis and alleviated disease phenotypes. Proceedings of the National Academy of Sciences of the United States of America, 108(46), 18808-18813. https://doi.org/10.1073/pnas.1104964108