{"doi":"10.1016/j.jbc.2025.110863","title":"The histone methyltransferase MLL1 complex inhibits expression of fetal hemoglobin","abstract":"Increasing fetal-type hemoglobin expression in adult erythroid cells holds promise in the treatment of sickle cell disease (SCD) and β-thalassemia. We have identified the MLL1 complex as a critical regulator of fetal and embryonic hemoglobin repression. Knockdowns of MEN1 and KMT2A , encoding essential components of the complex, caused a significant downregulation of BCL11A expression and a substantial increase in γ- and ε-globin mRNA levels in HUDEP-2 cells. Significant binding of MEN1 and KMT2A was readily detected at the promoter and a critical enhancer of BCL11A in HUDEP-2 cells, suggesting that BCL11A is a direct transcriptional target of the MLL1 complex. Consistent with these results, MEN1 or KMT2A knockdown in normal human CD34 + hematopoietic stem and progenitor cells induced to undergo erythroid differentiation also significantly decreased their BCL11A expression and increased their γ- and ε-globin expression and the production of F cells in the culture. Treatment of these cells with MENIN inhibitors yielded similar results and promoted erythroid differentiation with minimal effects on their growth. Moreover, treatment of CD34 + hematopoietic stem and progenitor cells from SCD patients with MENIN inhibitors substantially increased γ-globin expression in their erythroid progenies. These findings underscore a critical role of the MLL1 complex in regulating fetal and embryonic hemoglobin expression and suggest that MENIN inhibitors could offer a promising therapeutic approach for SCD and β-thalassemia.","journal":"Journal of Biological Chemistry","year":2025,"id":548013,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":1,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9572,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE292144"]},"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":1440764,"name":"B K Gudmundsdóttir","orcid":"0009-0004-6967-545X","position":1,"is_corresponding":false},{"id":314495,"name":"Kristbjorn O. Gudmundsson","orcid":"0000-0002-5995-2263","position":2,"is_corresponding":false},{"id":373497,"name":"Kartik R. Roy","orcid":"0000-0002-9774-5687","position":3,"is_corresponding":false},{"id":320686,"name":"John F. Tisdale","orcid":"0000-0002-8535-9439","position":4,"is_corresponding":false},{"id":1440765,"name":"Yang Du","orcid":"0000-0003-2773-1113","position":5,"is_corresponding":false},{"id":1441247,"name":"Yufen Han","orcid":null,"position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T02:53:53.962932Z","pmid":"41161385","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":[]}