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

Abstract

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.

• Authors: Bon Q Trinh, Simone Ummarino, Yanzhou Zhang, Alexander K Ebralidze, Mahmoud A Bassal, Tuan M Nguyen, Gerwin Heller, Rory Coffey, Danielle E Tenen, Emiel van der Kouwe, Emiliano Fabiani, Carmelo Gurnari, Chan-Shuo Wu, Vladimir Espinosa Angarica, Henry Yang, Sisi Chen, Hong Zhang, Abby R Thurm, Francisco Marchi, Elena Levantini, Philipp B Staber, Pu Zhang, Maria Teresa Voso, Pier Paolo Pandolfi, Susumu S Kobayashi, Li Chai, Annalisa Di Ruscio, Daniel G Tenen
• Journal: Blood (Blood) Vol. 138 Issue 15 Pg. 1331-1344 (10 14 2021) ISSN: 1528-0020 [Electronic] United States
• PMID: 33971010 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2021 by The American Society of Hematology.

Chemical References

• Core Binding Factor Alpha 2 Subunit
• Oncogene Proteins, Fusion
• RNA, Long Noncoding
• RUNX1 Translocation Partner 1 Protein
• RUNX1 protein, human
• RUNX1T1 protein, human

Topics

• Cell Line, Tumor
• Core Binding Factor Alpha 2 Subunit (genetics)
• Gene Expression Regulation, Leukemic
• Humans
• Leukemia, Myeloid, Acute (genetics)
• Oncogene Proteins, Fusion (genetics)
• RNA, Long Noncoding (genetics)
• RUNX1 Translocation Partner 1 Protein (genetics)
• Transcriptional Activation