{"doi":"10.3389/fcell.2022.992714","title":"A direct comparison between AML1-ETO and ETO2-GLIS2 leukemia fusion proteins reveals context-dependent binding and regulation of target genes and opposite functions in cell differentiation","abstract":"The ETO-family transcriptional corepressors, including ETO, ETO2, and MTGR1, are all involved in leukemia-causing chromosomal translocations. In every case, an ETO-family corepressor acquires a DNA-binding domain (DBD) to form a typical transcription factor-the DBD binds to DNA, while the ETO moiety manifests transcriptional activity. A directly comparative study of these \"homologous\" fusion transcription factors may clarify their similarities and differences in regulating transcription and leukemogenesis. Here, we performed a side-by-side comparison between AML1-ETO and ETO2-GLIS2, the most common fusion proteins in M2-and M7-subtypes of acute myeloid leukemia, respectively, by inducible expression of them in U937 leukemia cells. We found that, although AML1-ETO and ETO2-GLIS2 can use their own DBDs to bind DNA, they share a large proportion of genome-wide binding regions dependent on other cooperative transcription factors, including the ETS-, bZIP- and bHLH-family proteins. AML1-ETO acts as either transcriptional repressor or activator, whereas ETO2-GLIS2 mainly acts as activator. The repressor-versus-activator functions of AML1-ETO might be determined by the abundance of cooperative transcription factors/cofactors on the target genes. Importantly, AML1-ETO and ETO2-GLIS2 differentially regulate key transcription factors in myeloid differentiation including PU.1 and C/EBPβ. Consequently, AML1-ETO inhibits, but ETO2-GLIS2 facilitates, myeloid differentiation of U937 cells. This function of ETO2-GLIS2 is reminiscent of a similar effect of MLL-AF9 as previously reported. Taken together, this directly comparative study between AML1-ETO and ETO2-GLIS2 in the same cellular context provides insights into context-dependent transcription regulatory mechanisms that may underlie how these seemingly \"homologous\" fusion transcription factors exert distinct functions to drive different subtypes of leukemia.","journal":"Frontiers in Cell and Developmental Biology","year":2022,"id":286679,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.96,"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":966420,"name":"Xiao-Lin Wang","orcid":null,"position":1,"is_corresponding":false},{"id":734626,"name":"Chunhui Xu","orcid":"0000-0002-3836-3179","position":2,"is_corresponding":false},{"id":965993,"name":"Na Liu","orcid":"0000-0002-4405-4583","position":3,"is_corresponding":false},{"id":965994,"name":"Ling Zhang","orcid":"0000-0003-3963-2702","position":4,"is_corresponding":false},{"id":965995,"name":"Yuming Zhang","orcid":"0009-0007-9710-7726","position":5,"is_corresponding":false},{"id":734629,"name":"Yinyin Xie","orcid":"0009-0008-3777-7186","position":6,"is_corresponding":false},{"id":734627,"name":"Yuanliang Zhang","orcid":"0000-0001-5847-0978","position":7,"is_corresponding":false},{"id":734637,"name":"Qiuhua Huang","orcid":"0000-0002-5701-0117","position":8,"is_corresponding":false},{"id":734636,"name":"Lan Wang","orcid":"0000-0003-3545-5059","position":9,"is_corresponding":false},{"id":734638,"name":"Chen Zhu","orcid":"0000-0002-4548-047X","position":10,"is_corresponding":false},{"id":734639,"name":"Sai‐Juan Chen","orcid":"0000-0003-3789-1284","position":11,"is_corresponding":false},{"id":246358,"name":"Robert G. Roeder","orcid":"0000-0003-3865-8572","position":12,"is_corresponding":false},{"id":901928,"name":"Shuhong Shen","orcid":"0000-0002-0001-642X","position":13,"is_corresponding":false},{"id":667969,"name":"Kai Xue","orcid":"0000-0003-0919-9231","position":14,"is_corresponding":false},{"id":734641,"name":"Xiao‐Jian Sun","orcid":"0000-0001-8826-4614","position":15,"is_corresponding":false},{"id":566320,"name":"Yifan Zhang","orcid":"0000-0001-6488-6232","position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":null,"created_at":"2026-07-19T00:29:52.825777Z","pmid":"36158200","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":[]}