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, Catriona H.M. Jamieson

Research output: Contribution to journalArticle

17 Scopus citations

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.

Original languageEnglish (US)
Article number1922
JournalNature communications
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2017

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Lazzari, E., Mondala, P. K., Santos, N. D., Miller, A. C., Pineda, G., Jiang, Q., Leu, H., Ali, S. A., Ganesan, A. P., Wu, C. N., Costello, C., Minden, M., Chiaramonte, R., Stewart, A. K., Crews, L. A., & Jamieson, C. H. M. (2017). Alu-dependent RNA editing of GLI1 promotes malignant regeneration in multiple myeloma. Nature communications, 8(1), [1922]. https://doi.org/10.1038/s41467-017-01890-w