A MIR17HG-derived Long Noncoding RNA Provides an Essential Chromatin Scaffold for Protein Interaction and Myeloma Growth.

TitleA MIR17HG-derived Long Noncoding RNA Provides an Essential Chromatin Scaffold for Protein Interaction and Myeloma Growth.
Publication TypeJournal Article
Year of Publication2022
AuthorsMorelli E, Fulciniti M, Samur MK, Ribeiro C, Wert-Lamas L, Henninger JE, Gulla A, Samur AAktas, Todoerti K, Talluri S, Park WD, Federico C, Scionti F, Amodio N, Bianchi G, Johnstone M, Liu N, Gramegna D, Maisano D, Russo NA, Lin CY, Tai Y-T, Neri A, Chauhan D, Hideshima T, Shammas MA, Tassone P, Gryaznov S, Young R, Anderson KC, Novina CD, Loda M, Munshi NC
JournalBlood
Date Published2022 Sep 20
ISSN1528-0020
Abstract

Long noncoding RNAs (lncRNA) can drive tumorigenesis and are susceptible to therapeutic intervention. Here, we used a large-scale CRISPR interference viability screen to interrogate cell growth dependency to lncRNA genes in multiple myeloma (MM), and identified a prominent role for the miR-17-92 cluster host gene (MIR17HG). We show that a MIR17HG-derived lncRNA, named lnc-17-92, is the main mediator of cell growth dependency acting in a microRNA- and DROSHA- independent manner. Lnc-17-92 provides a chromatin scaffold for the functional interaction between c-MYC and WDR82, thus promoting the expression of ACACA, which encodes the rate-limiting enzyme of de novo lipogenesis acetyl-coA carboxylase 1 (ACC1). Targeting MIR17HG pre-RNA with clinically applicable antisense molecules disrupts the transcriptional and functional activities of lnc-17-92, causing potent anti-tumor effects both in vitro and in vivo in three pre-clinical animal models, including a clinically relevant PDX-NSG mouse model. This study establishes a novel oncogenic function of MIR17HG and provides potent inhibitors for translation to clinical trials.

DOI10.1182/blood.2022016892
Alternate JournalBlood
PubMed ID36126301
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Massimo Loda, M.D.

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