Myeloid lncRNA LOUP mediates opposing regulatory effects of RUNX1 and RUNX1-ETO in t(8;21) AML

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 trans...

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Veröffentlicht in:Blood 2021-10, Vol.138 (15), p.1331-1344
Hauptverfasser: 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.
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Sprache:eng
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Zusammenfassung: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. •lncRNA LOUP coordinates with RUNX1 to induce PU.1 long-range transcription, conferring myeloid differentiation and inhibiting cell growth.•RUNX1-ETO limits chromatin accessibility at the LOUP locus, causing inhibition of LOUP and PU.1 expression in t(8;21) AML. [Display omitted]
ISSN:0006-4971
1528-0020
1528-0020
DOI:10.1182/blood.2020007920