ADAR1 Activation Drives Leukemia Stem Cell Self-Renewal by Impairing Let-7 Biogenesis.
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.
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.
Maria Anna
MA
Zipeto
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.
Angela C
AC
Court
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.
Anil
A
Sadarangani
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.
Nathaniel P
NP
Delos Santos
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.
Larisa
L
Balaian
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
Hye-Jung
HJ
Chun
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.
Gabriel
G
Pineda
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.
Sheldon R
SR
Morris
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.
Cayla N
CN
Mason
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.
Ifat
I
Geron
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
Christian
C
Barrett
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.
Daniel J
DJ
Goff
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.
Russell
R
Wall
School of Medicine, University of California Riverside, Riverside, CA 92521, USA.
Maurizio
M
Pellecchia
Princess Margaret Hospital, Toronto, ON M5G 2M9, Canada.
Mark
M
Minden
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
Kelly A
KA
Frazer
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
Marco A
MA
Marra
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.
Leslie A
LA
Crews
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: q1jiang@ucsd.edu.
Qingfei
Q
Jiang
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: cjamieson@ucsd.edu.
Catriona H M
CHM
Jamieson
D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D000066673:Cell Self Renewal / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D053614:Janus Kinase 2 / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000473:pathology*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D017393:RNA Editing / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
C581634:BCR-ABL1 fusion protein, human; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C487931:mirnlet7 microRNA, human; D016044:Fusion Proteins, bcr-abl; C507924:JAK2 protein, human; D053614:Janus Kinase 2; C000595356:ADAR protein, human; D000243:Adenosine Deaminase