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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\u2019 heel whereby DUX4-r\u2013positive 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.<\/jats:p>","DOI":"10.1126\/sciadv.adi3771","type":"journal-article","created":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T13:58:22Z","timestamp":1694786302000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":3,"title":["DUX4-r exerts a neomorphic activity that depends on GTF2I in acute lymphoblastic leukemia"],"prefix":"10.1126","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7744-0598","authenticated-orcid":true,"given":"Daniele","family":"Campolungo","sequence":"first","affiliation":[{"name":"Gene Expression and Muscular Dystrophy Unit, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, 20132 Milano, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3267-650X","authenticated-orcid":true,"given":"Mara","family":"Salom\u00e9","sequence":"additional","affiliation":[{"name":"Gene Expression and Muscular Dystrophy Unit, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, 20132 Milano, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2399-885X","authenticated-orcid":true,"given":"Beatrice","family":"Biferali","sequence":"additional","affiliation":[{"name":"Gene Expression and Muscular Dystrophy Unit, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, 20132 Milano, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5731-5490","authenticated-orcid":true,"given":"Anna Sofia","family":"Tascini","sequence":"additional","affiliation":[{"name":"Center for Omics Sciences, IRCCS Ospedale San Raffaele, 20132 Milano, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3811-4121","authenticated-orcid":true,"given":"Davide","family":"Gabellini","sequence":"additional","affiliation":[{"name":"Gene Expression and Muscular Dystrophy Unit, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, 20132 Milano, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1400972"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3016.1996.tb00054.x"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/91.12.1051"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcm10173792"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3535"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3691"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11790"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-017-0515-y"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2017.183152"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3844"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3858"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3846"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw141"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-25963-z"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-10637-8"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2013.277"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.22464"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V110.11.691.691"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2018.204487"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2016.04.038"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1003947"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-018-0093-1"},{"key":"e_1_3_2_24_2","first-page":"4419","article-title":"Model systems of DUX4 expression recapitulate the transcriptional profile of FSHD cells","volume":"25","author":"Jagannathan S.","year":"2016","unstructured":"S.\u00a0Jagannathan, S. 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