Alu-dependent RNA Editing of GLI1 Promotes Malignant Regeneration in Multiple Myeloma

Overview

Journal Nat Commun

Specialty Biology

Date 2017 Dec 6

PMID 29203771

Citations 68

Authors

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

Affiliations

Soon will be listed here.

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.

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