TY - JOUR
T1 - Alu-dependent RNA editing of GLI1 promotes malignant regeneration in multiple myeloma
AU - Lazzari, Elisa
AU - Mondala, Phoebe K.
AU - Santos, Nathaniel Delos
AU - Miller, Amber C.
AU - Pineda, Gabriel
AU - Jiang, Qingfei
AU - Leu, Heather
AU - Ali, Shawn A.
AU - Ganesan, Anusha Preethi
AU - Wu, Christina N.
AU - Costello, Caitlin
AU - Minden, Mark
AU - Chiaramonte, Raffaella
AU - Stewart, A. Keith
AU - Crews, Leslie A.
AU - Jamieson, Catriona H.M.
N1 - Funding Information:
We wish to thank E.D. Ball and C. Mason at UC San Diego for technical assistance. This work was funded through the NCI (C.H.M.J., 1R21CA194679, R21CA189705, and 1R01CA205944), the NIDDK (1R01DK114468), the Multiple Myeloma Research Foundation (L.A.C.), the Blasker-Rose-Miah Fund of The San Diego Foundation (L.A. C.), the Leukemia & Lymphoma Society’s Quest for CURES Research Grant Program (C. H.M.J., 0754-14), the Italian Ministry of Education, University and Research (E.L., doctoral fellowship, co-mentor R.C.), the Strauss Family Foundation, the Moores Foundation, the Koman Family Foundation, the Sanford Stem Cell Clinical Center, and a NCI Cancer Center Support Grant to the Moores Cancer Center (P30-CA 023100).
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41467-017-01890-w
DO - 10.1038/s41467-017-01890-w
M3 - Article
C2 - 29203771
AN - SCOPUS:85037038486
SN - 2041-1723
VL - 8
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1922
ER -