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ADAR1 Activation Drives Leukemia Stem Cell Self-Renewal by Impairing Let-7 Biogenesis
- Zipeto, Maria Anna;
- Court, Angela C;
- Sadarangani, Anil;
- Santos, Nathaniel P Delos;
- Balaian, Larisa;
- Chun, Hye-Jung;
- Pineda, Gabriel;
- Morris, Sheldon R;
- Mason, Cayla N;
- Geron, Ifat;
- Barrett, Christian;
- Goff, Daniel J;
- Wall, Russell;
- Pellecchia, Maurizio;
- Minden, Mark;
- Frazer, Kelly A;
- Marra, Marco A;
- Crews, Leslie A;
- Jiang, Qingfei;
- Jamieson, Catriona HM
- et al.
Published Web Location
https://doi.org/10.1016/j.stem.2016.05.004Abstract
Post-transcriptional adenosine-to-inosine RNA editing mediated by adenosine deaminase acting on RNA1 (ADAR1) promotes cancer progression and therapeutic resistance. However, ADAR1 editase-dependent mechanisms governing leukemia stem cell (LSC) generation have not been elucidated. In blast crisis chronic myeloid leukemia (BC CML), we show that increased JAK2 signaling and BCR-ABL1 amplification activate ADAR1. In a humanized BC CML mouse model, combined JAK2 and BCR-ABL1 inhibition prevents LSC self-renewal commensurate with ADAR1 downregulation. Lentiviral ADAR1 wild-type, but not an editing-defective ADAR1(E912A) mutant, induces self-renewal gene expression and impairs biogenesis of stem cell regulatory let-7 microRNAs. Combined RNA sequencing, qRT-PCR, CLIP-ADAR1, and pri-let-7 mutagenesis data suggest that ADAR1 promotes LSC generation via let-7 pri-microRNA editing and LIN28B upregulation. A small-molecule tool compound antagonizes ADAR1's effect on LSC self-renewal in stromal co-cultures and restores let-7 biogenesis. Thus, ADAR1 activation represents a unique therapeutic vulnerability in LSCs with active JAK2 signaling.
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