{"doi":"10.1182/blood.2024028136","title":"A novel mouse model of hemoglobin SC disease reveals mechanisms underlying beneficial effects of hydroxyurea","abstract":"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-globin expression was switched off, and continued postnatally, we could induce HbF in both HbSC and HbSS mice (higher HbF in HbSS vs HbSC mice). Minimal increases in HbF (∼1%) improved HbSC RBC hydration. Peak HbF levels of 7% in HbSC mice abrogated sickling. Overall, this HbSC model will help bridge the knowledge gap in mechanistic/therapeutic studies in this neglected disease.","journal":"Blood","year":2025,"id":518326,"datarank":0.32958368660043297,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"self_citation_contribution":0.32958368660043297,"citation_network_contribution":0.0,"self_endowment_contribution":0.32958368660043297,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.959,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1247100,"name":"Mengna Chi","orcid":"0000-0001-7439-1663","position":1,"is_corresponding":false},{"id":1253575,"name":"Zachery Oestreicher","orcid":"0000-0001-5887-653X","position":2,"is_corresponding":false},{"id":757308,"name":"Masahide Sakabe","orcid":"0000-0003-0851-296X","position":3,"is_corresponding":false},{"id":479394,"name":"Katie Seu","orcid":"0000-0002-0192-7209","position":4,"is_corresponding":false},{"id":1385751,"name":"Zhenqi Zhu","orcid":"0000-0001-7441-1433","position":5,"is_corresponding":false},{"id":1162395,"name":"Harsimran Kaur","orcid":"0000-0003-2667-1091","position":6,"is_corresponding":false},{"id":1386227,"name":"Anifat Tijani","orcid":null,"position":7,"is_corresponding":false},{"id":458434,"name":"Mei Xin","orcid":"0000-0002-5732-7501","position":8,"is_corresponding":false},{"id":1386228,"name":"Amy Shova","orcid":null,"position":9,"is_corresponding":false},{"id":87808,"name":"Kenneth D. Greis","orcid":"0000-0002-5316-3351","position":10,"is_corresponding":false},{"id":695901,"name":"Tim M. Townes","orcid":null,"position":11,"is_corresponding":false},{"id":874099,"name":"József Balla","orcid":"0000-0001-7923-2645","position":12,"is_corresponding":false},{"id":676148,"name":"Katherine VandenHeuvel","orcid":null,"position":13,"is_corresponding":false},{"id":87797,"name":"Yueh-Chiang Hu","orcid":"0000-0002-7992-0525","position":14,"is_corresponding":false},{"id":320800,"name":"Punam Malik","orcid":"0000-0002-8942-2108","position":15,"is_corresponding":false},{"id":467039,"name":"Tahereh Setayesh","orcid":"0000-0002-1770-208X","position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:49:09.679930Z","pmid":"40324066","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}