A MIR17HG-derived Long Noncoding RNA Provides an Essential Chromatin Scaffold for Protein Interaction and Myeloma Growth
Name
blood.2022016892.pdf
Description
Published version
Size
4.4 MB
Format
Adobe PDF
Checksum (MD5)
8da666ddb002d0c63d8a5cbe29386d92
Author(s)
Young, Richard
Date Issued
September 20, 2022
Journal
Blood
Publisher
American Society of Hematology
Citation
Young, Richard. 2022. "A MIR17HG-derived Long Noncoding RNA Provides an Essential Chromatin Scaffold for Protein Interaction and Myeloma Growth." Blood.
Version
Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1182/blood.2022016892
