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Myeloid lncRNA LOUP mediates opposing regulatory effects of RUNX1 and RUNX1-ETO in t(8;21) AML.
Trinh, Bon Q; Ummarino, Simone; Zhang, Yanzhou; Ebralidze, Alexander K; Bassal, Mahmoud A; Nguyen, Tuan M; Heller, Gerwin; Coffey, Rory; Tenen, Danielle E; van der Kouwe, Emiel; Fabiani, Emiliano; Gurnari, Carmelo; Wu, Chan-Shuo; Angarica, Vladimir Espinosa; Yang, Henry; Chen, Sisi; Zhang, Hong; Thurm, Abby R; Marchi, Francisco; Levantini, Elena; Staber, Philipp B; Zhang, Pu; Voso, Maria Teresa; Pandolfi, Pier Paolo; Kobayashi, Susumu S; Chai, Li; Di Ruscio, Annalisa; Tenen, Daniel G.
Afiliación
  • Trinh BQ; Harvard Medical School Initiative for RNA Medicine, Harvard Medical School, Boston, MA.
  • Ummarino S; Harvard Medical School Initiative for RNA Medicine, Harvard Medical School, Boston, MA.
  • Zhang Y; Harvard Medical School Initiative for RNA Medicine, Harvard Medical School, Boston, MA.
  • Ebralidze AK; Harvard Medical School Initiative for RNA Medicine, Harvard Medical School, Boston, MA.
  • Bassal MA; Harvard Stem Cell Institute, Harvard University, Boston, MA.
  • Nguyen TM; Cancer Science Institute of Singapore, National University of Singapore, Singapore.
  • Heller G; Harvard Medical School Initiative for RNA Medicine, Harvard Medical School, Boston, MA.
  • Coffey R; Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA.
  • Tenen DE; Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
  • van der Kouwe E; Harvard Medical School Initiative for RNA Medicine, Harvard Medical School, Boston, MA.
  • Fabiani E; Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
  • Gurnari C; Division of Hematology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
  • Wu CS; Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
  • Angarica VE; Saint Camillus International University of Health Sciences, Rome, Italy.
  • Yang H; Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
  • Chen S; Cancer Science Institute of Singapore, National University of Singapore, Singapore.
  • Zhang H; Cancer Science Institute of Singapore, National University of Singapore, Singapore.
  • Thurm AR; Cancer Science Institute of Singapore, National University of Singapore, Singapore.
  • Marchi F; Harvard Medical School Initiative for RNA Medicine, Harvard Medical School, Boston, MA.
  • Levantini E; Harvard Medical School Initiative for RNA Medicine, Harvard Medical School, Boston, MA.
  • Staber PB; Harvard Stem Cell Institute, Harvard University, Boston, MA.
  • Zhang P; Stanford University School of Medicine, Stanford, CA.
  • Voso MT; Harvard Stem Cell Institute, Harvard University, Boston, MA.
  • Pandolfi PP; University of Florida, Gainesville, FL.
  • Kobayashi SS; Harvard Medical School Initiative for RNA Medicine, Harvard Medical School, Boston, MA.
  • Chai L; Harvard Stem Cell Institute, Harvard University, Boston, MA.
  • Di Ruscio A; Institute of Biomedical Technologies, National Research Council (CNR), Area della Ricerca di Pisa, Pisa, Italy.
  • Tenen DG; Division of Hematology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
Blood ; 138(15): 1331-1344, 2021 10 14.
Article en En | MEDLINE | ID: mdl-33971010
The mechanism underlying cell type-specific gene induction conferred by ubiquitous transcription factors as well as disruptions caused by their chimeric derivatives in leukemia is not well understood. Here, we investigate whether RNAs coordinate with transcription factors to drive myeloid gene transcription. In an integrated genome-wide approach surveying for gene loci exhibiting concurrent RNA and DNA interactions with the broadly expressed Runt-related transcription factor 1 (RUNX1), we identified the long noncoding RNA (lncRNA) originating from the upstream regulatory element of PU.1 (LOUP). This myeloid-specific and polyadenylated lncRNA induces myeloid differentiation and inhibits cell growth, acting as a transcriptional inducer of the myeloid master regulator PU.1. Mechanistically, LOUP recruits RUNX1 to both the PU.1 enhancer and the promoter, leading to the formation of an active chromatin loop. In t(8;21) acute myeloid leukemia (AML), wherein RUNX1 is fused to ETO, the resulting oncogenic fusion protein, RUNX1-ETO, limits chromatin accessibility at the LOUP locus, causing inhibition of LOUP and PU.1 expression. These findings highlight the important role of the interplay between cell-type-specific RNAs and transcription factors, as well as their oncogenic derivatives in modulating lineage-gene activation and raise the possibility that RNA regulators of transcription factors represent alternative targets for therapeutic development.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda / Proteínas de Fusión Oncogénica / Subunidad alfa 2 del Factor de Unión al Sitio Principal / ARN Largo no Codificante / Proteína 1 Compañera de Translocación de RUNX1 Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Blood Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda / Proteínas de Fusión Oncogénica / Subunidad alfa 2 del Factor de Unión al Sitio Principal / ARN Largo no Codificante / Proteína 1 Compañera de Translocación de RUNX1 Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Blood Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos