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

• DOI: 10.1182/blood.2020007920
• Publication Date: 2021-05-10T21:00:56Z
• Authors: Bon Q. Trinh; Simone Ummarino; Yanzhou Zhang; Alexander K. Ebra...; 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...; 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
• Keywords: Transcriptional Activation; 0301 basic medicine; 572; Oncogene Proteins, Fusion; Gene Expression Regulation, Leukemic; PU.1; leukemia; non coding RNA; Settore MED/15 - MALATTIE DEL SANGUE; Leukemia, Myeloid, Acute; 03 medical and health sciences; RUNX1 Translocation Partner 1 Protein; Cell Line, Tumor; Core Binding Factor Alpha 2 Subunit; chromatin; Humans; RNA, Long Noncoding; gene regulation; transcription factor

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.