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Published on: April 25, 2018
A MIR17HG-derived long noncoding RNA provides an essential chromatin scaffold for protein interaction and myeloma
Eugenio Morelli1,2, Mariateresa Fulciniti1,2, Mehmet K Samur1,2
1Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA.
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.
Insights
Long noncoding RNA MIR17HG drives multiple myeloma growth by regulating lipogenesis. Targeting its pre-RNA with antisense molecules shows potent antitumor effects in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Long noncoding RNAs (lncRNAs) are increasingly recognized for their roles in cancer development.
- Therapeutic targeting of lncRNAs presents a promising avenue for cancer treatment.
- Multiple myeloma (MM) is a hematologic malignancy with complex genetic underpinnings.
Purpose of the Study:
- To identify lncRNAs crucial for multiple myeloma cell growth using a large-scale CRISPR interference screen.
- To elucidate the oncogenic mechanism of the identified lncRNA, MIR17HG, and its derivatives.
- To evaluate the therapeutic potential of targeting MIR17HG in preclinical MM models.
Main Methods:
- Conducted a large-scale CRISPR interference viability screen to identify lncRNA dependencies in MM.
- Characterized the function of MIR17HG-derived lncRNA (lnc-17-92) in a microRNA- and DROSHA-independent manner.
- Investigated the molecular mechanism involving c-MYC, WDR82, and ACACA expression.
- Tested antisense molecules targeting MIR17HG pre-RNA in vitro and in vivo preclinical models, including patient-derived xenografts.
Main Results:
- Identified MIR17HG as a key driver of cell-growth dependency in multiple myeloma.
- Demonstrated that lnc-17-92, derived from MIR17HG, promotes ACACA expression and de novo lipogenesis.
- Showed that targeting MIR17HG pre-RNA with antisense molecules effectively inhibits lnc-17-92 activity.
- Observed significant antitumor effects in vitro and in vivo across multiple preclinical MM models.
Conclusions:
- MIR17HG plays a novel oncogenic role in multiple myeloma through the lnc-17-92 transcript.
- The lnc-17-92 mechanism involves facilitating c-MYC and WDR82 interaction to promote lipogenesis.
- Antisense-mediated targeting of MIR17HG pre-RNA offers a potent therapeutic strategy for multiple myeloma with clinical translation potential.
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