{"doi":"10.1016/j.exphem.2022.07.005","title":"Hydroxyurea Decouples Persistent F-Cell Elevation and Induction of γ-Globin","abstract":"•Townes humanized knock-in mouse model recapitulates human globin gene switching.•Silencing of γ-globin is completed during postnatal development checkpoints 2 to 4 after birth of Townes mice.•Normal murine developmental erythropoiesis coincides with human globin gene switching in the Townes mouse model.•Hydroxyurea suppresses erythropoiesis in Townes mice to create an early persistent F-cell phenotype without re-activating γ-globin transcription.•Value of Townes mouse model as pre-clinical model for pharmacologic fetal hemoglobin inducers is dependent on specific mechanism of action of the drug. Mechanisms that control the fetal-to-adult hemoglobin switch are attractive therapeutic targets in sickle cell disease. In this study, we investigated developmental γ-globin silencing in the Townes humanized knock-in mouse model, which harbors a construct containing the human γ-, βA-, and βS-globin genes, and examined the utility of this model in evaluation of pharmacologic induction of fetal hemoglobin (HbF). We studied mouse pups on the day of delivery (P0) to 28 days after birth (P28). Regardless of the hemoglobin genotype (SS, AS, or AA), the proportion of F cells in peripheral blood was 100% at P0, declined sharply to 20% at P2, and was virtually undetectable at P14. Developmental γ-globin silencing in Townes mice was complete at P4 in association with significantly increased BCL11A expression in the primary erythropoietic organs of the mouse. Hydroxyurea given at P2 significantly sustained elevated percentages of F cells in mice at P14. However, the percentage of F cells declined at P14 for treatment begun at P4. A lack of augmentation of γ-globin mRNA in erythroid tissues suggests that the apparent increase in HbF in red cells caused by hydroxyurea was not due to sustained or re-activation of γ-globin transcription, but was instead a function of erythropoiesis suppression. Thus, we provide new details of the hemoglobin switch in the Townes murine model that recapitulates postnatal γ- to β-globin switch in humans and identify the myelosuppressive toxicity of hydroxyurea as a superseding factor in interpreting pharmacologic induction of HbF. Mechanisms that control the fetal-to-adult hemoglobin switch are attractive therapeutic targets in sickle cell disease. In this study, we investigated developmental γ-globin silencing in the Townes humanized knock-in mouse model, which harbors a construct containing the human γ-, βA-, and βS-globin genes, and examined the utility of this model in evaluation of pharmacologic induction of fetal hemoglobin (HbF). We studied mouse pups on the day of delivery (P0) to 28 days after birth (P28). Regardless of the hemoglobin genotype (SS, AS, or AA), the proportion of F cells in peripheral blood was 100% at P0, declined sharply to 20% at P2, and was virtually undetectable at P14. Developmental γ-globin silencing in Townes mice was complete at P4 in association with significantly increased BCL11A expression in the primary erythropoietic organs of the mouse. Hydroxyurea given at P2 significantly sustained elevated percentages of F cells in mice at P14. However, the percentage of F cells declined at P14 for treatment begun at P4. A lack of augmentation of γ-globin mRNA in erythroid tissues suggests that the apparent increase in HbF in red cells caused by hydroxyurea was not due to sustained or re-activation of γ-globin transcription, but was instead a function of erythropoiesis suppression. Thus, we provide new details of the hemoglobin switch in the Townes murine model that recapitulates postnatal γ- to β-globin switch in humans and identify the myelosuppressive toxicity of hydroxyurea as a superseding factor in interpreting pharmacologic induction of HbF. Globin chain switching occurs in vertebrates to generate different forms of the tetrameric protein hemoglobin during development. In humans, the switch from γ-globin to β-globin occurs in the first few months after birth when fetal hemoglobin (HbF) i","journal":"Experimental Hematology","year":2022,"id":278713,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9414,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":951297,"name":"Danielle Crosby","orcid":"0000-0001-6051-4087","position":1,"is_corresponding":false},{"id":951723,"name":"Valerie Miller","orcid":null,"position":2,"is_corresponding":false},{"id":423330,"name":"Frances Weidert","orcid":null,"position":3,"is_corresponding":false},{"id":422530,"name":"Solomon F. Ofori‐Acquah","orcid":"0000-0001-5000-3048","position":4,"is_corresponding":false},{"id":392849,"name":"Aisha L. Walker","orcid":"0000-0001-8604-6162","position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":null,"created_at":"2026-07-19T00:28:47.357993Z","pmid":"35843392","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":[]}