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

Maria Anna Zipeto, Angela C. Court, Anil Sadarangani, Nathaniel P. Delos Santos, Larisa Balaian, Hye Jung Chun, Gabriel Pineda, Sheldon R. Morris, Cayla N. Mason, Ifat Geron, Christian Barrett, Daniel J. Goff, Russell Wall, Maurizio Pellecchia, Mark Minden, Kelly A. Frazer, Marco A. Marra, Leslie A. Crews, Qingfei Jiang*, Catriona H.M. Jamieson

*Autor correspondiente de este trabajo

Resultado de la investigación: Contribución a una revistaArtículorevisión exhaustiva

125 Citas (Scopus)

Resumen

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<sup>E912A</sup> 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.
Idioma originalInglés
Páginas (desde-hasta)177-191
Número de páginas15
PublicaciónCell Stem Cell
Volumen19
N.º2
DOI
EstadoPublicada - 4 ago. 2016
Publicado de forma externa

Nota bibliográfica

Publisher Copyright:
© 2016 Elsevier Inc.

Palabras clave

  • Adenosine Deaminase
  • Animals
  • Base Sequence
  • Cell Self Renewal
  • Fusion Proteins
  • bcr-abl
  • Gene Expression Regulation
  • Leukemic
  • Janus Kinase 2
  • Leukemia
  • Myelogenous
  • Chronic
  • BCR-ABL Positive
  • Mice
  • MicroRNAs
  • Neoplastic Stem Cells
  • RNA Editing
  • RNA-Binding Proteins
  • Signal Transduction

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