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

被引：25

作者：

Morelli, Eugenio ^{[1
,2
]}

Fulciniti, Mariateresa ^{[1
,2
]}

Samur, Mehmet K. ^{[1
,2
]}

Ribeiro, Caroline F. ^{[3
]}

Wert-Lamas, Leon ^{[4
]}

Henninger, Jon E. ^{[5
]}

Gulla, Annamaria ^{[1
,2
]}

Aktas-Samur, Anil ^{[1
,2
]}

Todoerti, Katia ^{[6
]}

Talluri, Srikanth ^{[1
,2
,7
]}

Park, Woojun D. ^{[8
]}

Federico, Cinzia ^{[9
]}

Scionti, Francesca ^{[9
,10
]}

Amodio, Nicola ^{[9
]}

Bianchi, Giada ^{[1
,2
]}

Johnstone, Megan ^{[1
]}

Liu, Na ^{[1
]}

Gramegna, Doriana ^{[1
,2
]}

Maisano, Domenico ^{[1
,2
]}

Russo, Nicola A. ^{[11
]}

Lin, Charles ^{[2
]}

Tai, Yu-Tzu ^{[1
]}

Neri, Antonino ^{[6
,12
,13
]}

Chauhan, Dharminder ^{[1
,2
]}

Hideshima, Teru ^{[1
,2
]}

Shammas, Masood A. ^{[1
,2
,7
]}

Tassone, Pierfrancesco ^{[9
]}

Gryaznov, Sergei ^{[14
]}

Young, Richard A.

Anderson, Kenneth C. ^{[1
,2
]}

Novina, Carl D. ^{[4
]}

Loda, Massimo ^{[3
]}

Munshi, Nikhil C. ^{[1
,2
,7
]}

机构：

[1] Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Dept Med Oncol, Boston, MA USA

[2] Harvard Med Sch, Boston, MA USA

[3] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY USA

[4] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA USA

[5] MIT, Whitehead Inst Biomed Res, Cambridge, MA USA

[6] Fdn Ca Granda IRCCS Policlin, Dept Hematol, Milan, Italy

[7] VA Boston Healthcare Syst, Boston, MA USA

[8] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX USA

[9] Magna Graecia Univ Catanzaro, Dept Clin & Expt Med, Catanzaro, Italy

[10] ASST Spedali Civili Brescia, Clin Res Dev & Phase I Unit, Brescia, Italy

[11] Ist Ric Genet G Salvatore Biogem scarl, Avellino, Italy

[12] Univ Milan, Dept Oncol & Hemato Oncol, Milan, Italy

[13] Azienda USL IRCCS Reggio Emilia, Sci Directorate, Reggio Emilia, Italy

[14] Maia Biotechnol lnc, Chicago, IL USA

来源：

BLOOD | 2023年 / 141卷 / 04期

关键词：

MULTIPLE-MYELOMA; IN-VITRO; MYC; GENOMICS; TARGET; IRF4; AMPLIFICATION; CLUSTER; CANCER; LNCRNA;

D O I：

10.1182/blood.2022016892

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：391 / 405

页数：15

共 66 条

[31] Antisense-Mediated Transcript Knockdown Triggers Premature Transcription Termination [J].