[HTML][HTML] Translational repression of HIF2α expression in mice with Chuvash polycythemia reverses polycythemia
MC Ghosh, DL Zhang, H Ollivierre… - The Journal of …, 2018 - Am Soc Clin Investig
MC Ghosh, DL Zhang, H Ollivierre, MA Eckhaus, TA Rouault
The Journal of Clinical Investigation, 2018•Am Soc Clin InvestigChuvash 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 …
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 …
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.
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