{"doi":"10.1126/sciadv.adi3771","title":"DUX4-r exerts a neomorphic activity that depends on GTF2I in acute lymphoblastic leukemia","abstract":"Translocations producing rearranged versions of the transcription factor double homeobox 4 (DUX4-r) are one of the most frequent causes of B cell acute lymphoblastic leukemia (B-ALL). DUX4-r retains the DNA binding domain of wild-type DUX4 but is truncated on the C-terminal transcription activation domain. The precise mechanism through which DUX4-r causes leukemia is unknown, and no targeted therapy is currently available. We found that the rearrangement leads to both a loss and a gain of function in DUX4-r. Loss of CBP/EP300 transcriptional coactivator interaction leads to an inability to bind and activate repressed chromatin. Concurrently, a gain of interaction with the general transcription factor 2 I (GTF2I) redirects DUX4-r toward leukemogenic targets. This neomorphic activity exposes an Achilles' heel whereby DUX4-r-positive leukemia cells are exquisitely sensitive to GTF2I targeting, which inhibits DUX4-r leukemogenic activity. Our work elucidates the molecular mechanism through which DUX4-r causes leukemia and suggests a possible therapeutic avenue tailored to this B-ALL subtype.","journal":"Science Advances","year":2023,"id":383711,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9527,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1150768,"name":"Mara Salomè","orcid":"0000-0003-3267-650X","position":1,"is_corresponding":false},{"id":1150769,"name":"Beatrice Biferali","orcid":"0000-0002-2399-885X","position":2,"is_corresponding":false},{"id":1150770,"name":"Anna Sofia Tascini","orcid":"0000-0001-5731-5490","position":3,"is_corresponding":false},{"id":658066,"name":"Davide Gabellini","orcid":"0000-0002-3811-4121","position":4,"is_corresponding":false},{"id":1150767,"name":"Daniele Campolungo","orcid":"0000-0001-7744-0598","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-19T01:17:29.050285Z","pmid":"37713484","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":[]}