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

Zipeto, Maria Anna; Court, Angela C.; Sadarangani, Anil; Delos Santos, Nathaniel P.; 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; et. al.


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 wildtype, 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-micro-RNA 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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Título según WOS: ID WOS:000381622000012 Not found in local WOS DB
Título de la Revista: CELL STEM CELL
Volumen: 19
Número: 2
Editorial: Cell Press
Fecha de publicación: 2016
Página de inicio: 177
Página final: 191


Notas: ISI