| Autor: |
Eugenio Morelli, Mariateresa Fulciniti, Mehmet K. Samur, Caroline F. Ribeiro, Leon Wert-Lamas, Jon E. Henninger, Annamaria Gullà, Anil Aktas-Samur, Katia Todoerti, Srikanth Talluri, Woojun D. Park, Cinzia Federico, Francesca Scionti, Nicola Amodio, Giada Bianchi, Megan Johnstone, Na Liu, Doriana Gramegna, Nicola A. Russo, Charles Lin, Yu-Tzu Tai, Antonino Neri, Dharminder Chauhan, Teru Hideshima, Masood A. Shammas, Pierfrancesco Tassone, Sergei Gryaznov, Richard A. Young, Kenneth C. Anderson, Carl D. Novina, Massimo Loda, Nikhil C. Munshi |
| Rok vydání: |
2021 |
| Popis: |
SUMMARYLong noncoding RNAs (lncRNA) can drive the tumorigenesis and be susceptible to therapeutic intervention. To define the landscape of therapeutically actionable lncRNA dependencies in multiple myeloma (MM), we coupled our extensive lncRNA transcriptomic profile with lncRNA targeted CRISPR interference viability screen and identified RNA Regulator of Lipogenesis (RROL) as a leading lncRNA dependency in MM. RROL shares its origin with the microRNA locus MIR17HG, however supports the proliferation and survival of MM cells in a microRNA- and DROSHA- independent manner. We found that RROL provides a chromatin scaffold for the functional interaction between c-MYC and WDR82 to promote the regulation of the lipogenic pathways via the transcriptional control of the rate-limiting enzyme ACC1 in MM cells. Inhibition of RROL with clinically applicable antisense molecules disrupts its transcriptional and functional activities causing potent anti-tumor effects both in vitro and in vivo in two pre-clinical animal models. This study establishes lncRNA RROL as a therapeutically actionable dependency with a unique mechanism of action in support of myeloma cell growth. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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