{"doi":"10.1073/pnas.1818539116","title":"Homoharringtonine deregulates\n                    <i>MYC</i>\n                    transcriptional expression by directly binding NF-κB repressing factor","abstract":"<jats:p>\n                    Homoharringtonine (HHT), a known protein synthesis inhibitor, has an anti-myeloid leukemia effect and potentiates the therapeutic efficacy of anthracycline/cytarabine induction regimens for acute myelogenous leukemia (AML) with favorable and intermediate prognoses, especially in the t(8;21) subtype. Here we provide evidence showing that HHT inhibits the activity of leukemia-initiating cells (Lin\n                    <jats:sup>−</jats:sup>\n                    /Sca-1\n                    <jats:sup>−</jats:sup>\n                    /c-kit\n                    <jats:sup>+</jats:sup>\n                    ; LICs) in a t(8;21) murine leukemia model and exerts a down-regulating effect on MYC pathway genes in human t(8;21) leukemia cells (Kasumi-1). We discovered that NF-κB repressing factor (NKRF) is bound directly by HHT via the second double-strand RNA-binding motif (DSRM2) domain, which is the nuclear localization signal of NKRF. A series of deletion and mutagenesis experiments mapped HHT direct binding sites to K479 and C480 amino acids in the DSRM2 domain. HHT treatment shifts NKRF from the nucleus (including nucleoli) to the cytoplasm by occupying the DSRM2 domain, strengthens the p65–NKRF interaction, and interferes with p65-p50 complex formation, thereby attenuating the transactivation activity of p65 on the\n                    <jats:italic>MYC</jats:italic>\n                    gene. Moreover, HHT significantly decreases the expression of\n                    <jats:italic>KIT</jats:italic>\n                    , a frequently mutated and/or highly expressed gene in t(8;21) AML, in concert with MYC down-regulation. Our work thus identifies a mechanism of action of HHT that is different from, but acts in concert with, the known mode of action of this compound. These results justify further clinical testing of HHT in AML.\n                  </jats:p>","journal":"Proceedings of the National Academy of Sciences","year":2019,"id":675420,"datarank":3.0615376664397274,"base_score":4.736198448394496,"endowment":4.736198448394496,"self_citation_contribution":0.7104297672591745,"citation_network_contribution":2.351107899180553,"self_endowment_contribution":0.7104297672591745,"citer_contribution":2.351107899180553,"corpus_percentile":null,"corpus_rank":null,"citation_count":113,"citer_count":84,"citers_with_citation_signal":70,"citers_with_endowment":70,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1650870,"name":"Wei-Na Zhang","orcid":null,"position":1,"is_corresponding":false},{"id":810047,"name":"Bing Chen","orcid":"0000-0002-7042-8614","position":2,"is_corresponding":false},{"id":1764729,"name":"Wen-Da Xi","orcid":null,"position":3,"is_corresponding":false},{"id":1103249,"name":"Ying Lu","orcid":"0000-0002-0962-8588","position":4,"is_corresponding":false},{"id":90060,"name":"Jinyan Huang","orcid":"0000-0002-8053-0209","position":5,"is_corresponding":false},{"id":1764730,"name":"Yue-Ying Wang","orcid":null,"position":6,"is_corresponding":false},{"id":1037189,"name":"Jun Long","orcid":"0000-0003-0163-0007","position":7,"is_corresponding":false},{"id":1764731,"name":"Song-Fang Wu","orcid":null,"position":8,"is_corresponding":false},{"id":1764732,"name":"Yun-Xiang Zhang","orcid":null,"position":9,"is_corresponding":false},{"id":295488,"name":"Shu Wang","orcid":"0000-0001-9813-6069","position":10,"is_corresponding":false},{"id":1764733,"name":"Si-Xing Li","orcid":null,"position":11,"is_corresponding":false},{"id":1286958,"name":"Tong Yin","orcid":"0000-0002-3399-7092","position":12,"is_corresponding":false},{"id":341403,"name":"Min Lu","orcid":"0000-0002-7818-8344","position":13,"is_corresponding":false},{"id":1764734,"name":"Xiao-Dong Xi","orcid":null,"position":14,"is_corresponding":false},{"id":1764735,"name":"Jun-Min Li","orcid":null,"position":15,"is_corresponding":false},{"id":1764737,"name":"Kan-Kan Wang","orcid":null,"position":16,"is_corresponding":false},{"id":205884,"name":"Zhu Chen","orcid":null,"position":17,"is_corresponding":false},{"id":1764738,"name":"Sai-Juan Chen","orcid":null,"position":18,"is_corresponding":false},{"id":1764728,"name":"Xin-Jie Chen","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Homoharringtonine deregulates\n                    <i>MYC</i>\n                    transcriptional expression by directly binding NF-κB repressing factor","abstract":"<jats:p>\n                    Homoharringtonine (HHT), a known protein synthesis inhibitor, has an anti-myeloid leukemia effect and potentiates the therapeutic efficacy of anthracycline/cytarabine induction regimens for acute myelogenous leukemia (AML) with favorable and intermediate prognoses, especially in the t(8;21) subtype. Here we provide evidence showing that HHT inhibits the activity of leukemia-initiating cells (Lin\n                    <jats:sup>−</jats:sup>\n                    /Sca-1\n                    <jats:sup>−</jats:sup>\n                    /c-kit\n                    <jats:sup>+</jats:sup>\n                    ; LICs) in a t(8;21) murine leukemia model and exerts a down-regulating effect on MYC pathway genes in human t(8;21) leukemia cells (Kasumi-1). We discovered that NF-κB repressing factor (NKRF) is bound directly by HHT via the second double-strand RNA-binding motif (DSRM2) domain, which is the nuclear localization signal of NKRF. A series of deletion and mutagenesis experiments mapped HHT direct binding sites to K479 and C480 amino acids in the DSRM2 domain. HHT treatment shifts NKRF from the nucleus (including nucleoli) to the cytoplasm by occupying the DSRM2 domain, strengthens the p65–NKRF interaction, and interferes with p65-p50 complex formation, thereby attenuating the transactivation activity of p65 on the\n                    <jats:italic>MYC</jats:italic>\n                    gene. Moreover, HHT significantly decreases the expression of\n                    <jats:italic>KIT</jats:italic>\n                    , a frequently mutated and/or highly expressed gene in t(8;21) AML, in concert with MYC down-regulation. Our work thus identifies a mechanism of action of HHT that is different from, but acts in concert with, the known mode of action of this compound. These results justify further clinical testing of HHT in AML.\n                  </jats:p>","is_dataset_classified":null,"base_score":4.736198448394496,"endowment":4.736198448394496,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"30659143","pmcid":"PMC6369765","openalex_id":"https://openalex.org/W2911121386","authors":[],"funders":[{"funder_name":"National Natural Science Foundation of China","grant_id":"81470311","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"81670137","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"81270619","title":null},{"funder_name":"Samuel Waxman Cancer Research Foundation","grant_id":"No reference number","title":null},{"funder_name":"Academy of Medical Sciences","grant_id":"NAF\\R1\\180216","title":null}],"total_grants":5,"fwci":7.3907,"citation_percentile":0.9781892,"influential_citations":0,"citation_trend":[{"year":2018,"count":1},{"year":2019,"count":4},{"year":2020,"count":6},{"year":2021,"count":15},{"year":2022,"count":28},{"year":2023,"count":22},{"year":2024,"count":18},{"year":2025,"count":14},{"year":2026,"count":5}],"oa_status":"bronze","license":"https://www.pnas.org/site/aboutpnas/licenses.xhtml","oa_locations":[{"url":"https://www.pnas.org/content/pnas/116/6/2220.full.pdf","host_type":"journal"},{"url":"https://www.pnas.org/content/pnas/116/6/2220.full.pdf","host_type":"publisher"},{"url":"http://www.pnas.org/syndication/doi/10.1073/pnas.1818539116","host_type":"publisher"},{"url":"https://pnas.org/doi/pdf/10.1073/pnas.1818539116","host_type":"publisher"},{"url":"https://doi.org/10.1073/pnas.1818539116","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/30659143","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/6369765","host_type":"repository"}],"fields_of_study":["Acute Myeloid Leukemia Research","Retinoids in leukemia and cellular processes","RNA Research and Splicing"],"mesh_terms":["Homoharringtonine","Animals","Binding Sites","Chromosomes, Human, Pair 21","Chromosomes, Human, Pair 8","Disease Models, Animal","Dose-Response Relationship, Drug","Gene Expression Regulation","Humans","Protein Binding","Repressor Proteins","Transcription, Genetic","Translocation, Genetic","Biomarkers, Tumor","Leukemia, Myeloid, Acute","Genes, myc","Proto-Oncogene Proteins c-kit","Xenograft Model Antitumor Assays","Cell Line, Tumor","Mice","Transcription Factor RelA","Protein Interaction Domains and Motifs"],"keywords":["Homoharringtonine","Transactivation","Core binding factor","Cancer research","Myeloid leukemia","Leukemia","Gene","Chemistry","Transcription factor","Biology","Molecular biology","Genetics","Biochemistry","Kit","MYC","Acute myelogenous leukemia","Nf-κb Repressing Factor"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"doi"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-17T00:29:06.364675Z","pmid":null,"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":[]}