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Translational repression of HIF2α expression in mice with Chuvash polycythemia reverses polycythemia
Manik C. Ghosh, … , Michael A. Eckhaus, Tracey A. Rouault
Manik C. Ghosh, … , Michael A. Eckhaus, Tracey A. Rouault
Published February 26, 2018
Citation Information: J Clin Invest. 2018;128(4):1317-1325. https://doi.org/10.1172/JCI97684.
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Research Article Hematology

Translational repression of HIF2α expression in mice with Chuvash polycythemia reverses polycythemia

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Abstract

Chuvash polycythemia is an inherited disease caused by a homozygous germline VHLR200W mutation, which leads to impaired degradation of HIF2α, elevated levels of serum erythropoietin, and erythrocytosis/polycythemia. This phenotype is recapitulated by a mouse model bearing a homozygous VhlR200W mutation. We previously showed that iron-regulatory protein 1–knockout (Irp1-knockout) mice developed erythrocytosis/polycythemia through translational derepression of Hif2α, suggesting that IRP1 could be a therapeutic target to treat Chuvash polycythemia. Here, we fed VhlR200W mice supplemented with Tempol, a small, stable nitroxide molecule and observed that Tempol decreased erythropoietin production, corrected splenomegaly, normalized hematocrit levels, and increased the lifespans of these mice. We attribute the reversal of erythrocytosis/polycythemia to translational repression of Hif2α expression by Tempol-mediated increases in the IRE-binding activity of Irp1, as reversal of polycythemia was abrogated in VhlR200W mice in which Irp1 was genetically ablated. Thus, a new approach to the treatment of patients with Chuvash polycythemia may include dietary supplementation of Tempol, which decreased Hif2α expression and markedly reduced life-threatening erythrocytosis/polycythemia in the VhlR200W mice.

Authors

Manik C. Ghosh, De-Liang Zhang, Hayden Ollivierre, Michael A. Eckhaus, Tracey A. Rouault

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Figure 1

VhlR200W mice developed erythrocytosis/polycythemia at early ages.

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VhlR200W mice developed erythrocytosis/polycythemia at early ages.
(A) ...
(A) Hematocrit levels as determined by capillary tube centrifugation, (B) hemoglobin levels, and (C) RBC counts of VhlR200W mice (red circles) were significantly higher than those of their WT littermates (black circles) as early as 7 weeks of age. (A–C) P < 0.0001. To determine the P values, statistical analyses were performed using a 2-tailed paired t test. The mean ± SD is indicated in each panel.
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