A novel mouse model of hemoglobin SC disease reveals mechanisms underlying beneficial effects of hydroxyurea

作者：Tahereh Setayesh, Mengna Chi, Zachery Oestreicher, Masahide Sakabe, Katie Seu, Zhenqi Zhu, Harsimran Kaur, Anifat Tijani, Mei Xin, Amy Shova, Kenneth D. Greis, Tim M. Townes, József Balla, Katherine VandenHeuvel, Yueh‐Chiang Hu, Punam Malik · 发表于：Blood · 年份：2025 · DOI：10.1182/blood.2024028136 · 被引用次数：8 · 研究领域：Hemoglobinopathies and Related Disorders、Erythrocyte Function and Pathophysiology、Blood groups and transfusion

ABSTRACT: Sickle cell hemoglobin C (HbSC) disease results from compound heterozygosity of hemoglobin S (HbS) and hemoglobin C (HbC), comprising 30% of sickle cell disease (SCD). HbC induces red blood cell (RBC) dehydration/xerocytosis, which promotes sickling. HbSC-SCD causes significant morbidity despite being milder than homozygous HbSS-SCD. Current research/treatment strategies have focused on HbSS-SCD, whereas patients with HbSC are deprived of disease-modifying/transformative therapies because of lack of preclinical models. We generated HbSC mice, which resemble human HbSC-SCD: HbSC erythrocytes showed marked xerocytosis. Anemia, hemolysis, inflammation, and organ damage were milder than HbSS mice but hypoxia/reperfusion injury was similar. Retinopathy developed at higher frequency than HbSS mice (66.7% vs 16.7%; P < .05), as in patients with HbSC-SCD. Although HbSC RBCs sickled at lower oxygen tension than HbSS RBCs, they did not completely recover deformability after hypoxia/reoxygenation. Using the HbSC mice, we studied the mechanism by which hydroxyurea causes significant clinical benefit in patients with HbSC-SCD, despite minimal/modest increases in fetal Hb (HbF). We found hydroxyurea had distinct non-HbF and HbF effects. Hydroxyurea did not increase HbF in adult HbSC/HbSS mice but reduced RBC reactive oxygen species, ferryl Hb, and Heinz-body formation, thereby reducing membrane damage; however, RBC hydration was unaffected. When given to unborn pups before γ-glob...