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A MIR17HG-derived long noncoding RNA provides an essential chromatin scaffold for protein interaction and myeloma growth.


ABSTRACT: Long noncoding RNAs (lncRNAs) 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 an 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. Targeting MIR17HG pre-RNA with clinically applicable antisense molecules disrupts the transcriptional and functional activities of lnc-17-92, causing potent antitumor effects both in vitro and in vivo in 3 preclinical animal models, including a clinically relevant patient-derived xenograft NSG mouse model. This study establishes a novel oncogenic function of MIR17HG and provides potent inhibitors for translation to clinical trials.

SUBMITTER: Morelli E 

PROVIDER: S-EPMC10082365 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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A MIR17HG-derived long noncoding RNA provides an essential chromatin scaffold for protein interaction and myeloma growth.

Morelli Eugenio E   Fulciniti Mariateresa M   Samur Mehmet K MK   Ribeiro Caroline F CF   Wert-Lamas Leon L   Henninger Jon E JE   Gullà Annamaria A   Aktas-Samur Anil A   Todoerti Katia K   Talluri Srikanth S   Park Woojun D WD   Federico Cinzia C   Scionti Francesca F   Amodio Nicola N   Bianchi Giada G   Johnstone Megan M   Liu Na N   Gramegna Doriana D   Maisano Domenico D   Russo Nicola A NA   Lin Charles C   Tai Yu-Tzu YT   Neri Antonino A   Chauhan Dharminder D   Hideshima Teru T   Shammas Masood A MA   Tassone Pierfrancesco P   Gryaznov Sergei S   Young Richard A RA   Anderson Kenneth C KC   Novina Carl D CD   Loda Massimo M   Munshi Nikhil C NC  

Blood 20230101 4


Long noncoding RNAs (lncRNAs) 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 an 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 provide  ...[more]

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