Alu-dependent RNA editing of GLI1 promotes malignant regeneration in multiple myeloma

Elisa Lazzari, Phoebe K. Mondala, Nathaniel Delos Santos, Amber C. Miller, Gabriel Pineda, Qingfei Jiang, Heather Leu, Shawn A. Ali, Anusha-Preethi Ganesan, Christina N. Wu, Caitlin Costello, Mark Minden, Raffaella Chiaramonte, A. Keith Stewart, Leslie A. Crews () and Catriona H. M. Jamieson ()
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Elisa Lazzari: University of California, San Diego
Phoebe K. Mondala: University of California, San Diego
Nathaniel Delos Santos: University of California, San Diego
Amber C. Miller: Mayo Clinic
Gabriel Pineda: University of California, San Diego
Qingfei Jiang: University of California, San Diego
Heather Leu: University of California, San Diego
Shawn A. Ali: University of California, San Diego
Anusha-Preethi Ganesan: University of California, San Diego
Christina N. Wu: University of California, San Diego
Caitlin Costello: Moores Cancer Center at University of California, San Diego
Mark Minden: University Health Network
Raffaella Chiaramonte: University of Milan
A. Keith Stewart: Mayo Clinic
Leslie A. Crews: University of California, San Diego
Catriona H. M. Jamieson: University of California, San Diego

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: Abstract Despite novel therapies, relapse of multiple myeloma (MM) is virtually inevitable. Amplification of chromosome 1q, which harbors the inflammation-responsive RNA editase adenosine deaminase acting on RNA (ADAR)1 gene, occurs in 30–50% of MM patients and portends a poor prognosis. Since adenosine-to-inosine RNA editing has recently emerged as a driver of cancer progression, genomic amplification combined with inflammatory cytokine activation of ADAR1 could stimulate MM progression and therapeutic resistance. Here, we report that high ADAR1 RNA expression correlates with reduced patient survival rates in the MMRF CoMMpass data set. Expression of wild-type, but not mutant, ADAR1 enhances Alu-dependent editing and transcriptional activity of GLI1, a Hedgehog (Hh) pathway transcriptional activator and self-renewal agonist, and promotes immunomodulatory drug resistance in vitro. Finally, ADAR1 knockdown reduces regeneration of high-risk MM in serially transplantable patient-derived xenografts. These data demonstrate that ADAR1 promotes malignant regeneration of MM and if selectively inhibited may obviate progression and relapse.

Date: 2017
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DOI: 10.1038/s41467-017-01890-w

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