ADAR1 Activation Drives Leukemia Stem Cell Self-Renewal by Impairing Let-7 Biogenesis

  • Cell Stem Cell. 2016 Aug 4;19(2):177-191. doi: 10.1016/j.stem.2016.05.004.
Maria Anna Zipeto  1 ,  Angela C Court  1 ,  Anil Sadarangani  1 ,  Nathaniel P Delos Santos  1 ,  Larisa Balaian  1 ,  Hye-Jung Chun  2 ,  Gabriel Pineda  1 ,  Sheldon R Morris  1 ,  Cayla N Mason  1 ,  Ifat Geron  1 ,  Christian Barrett  3 ,  Daniel J Goff  1 ,  Russell Wall  1 ,  Maurizio Pellecchia  4 ,  Mark Minden  5 ,  Kelly A Frazer  3 ,  Marco A Marra  2 ,  Leslie A Crews  1 ,  Qingfei Jiang  6 ,  Catriona H M Jamieson  7
Affiliations
  • 1. Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • 2. Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
  • 3. Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
  • 4. School of Medicine, University of California Riverside, Riverside, CA 92521, USA.
  • 5. Princess Margaret Hospital, Toronto, ON M5G 2M9, Canada.
  • 6. Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: [email protected].
  • 7. Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: [email protected].
PMID: 27292188 DOI: 10.1016/j.stem.2016.05.004
Abstract

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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