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ADAR1 Activation Drives Leukemia Stem Cell Self-Renewal by Impairing Let-7 Biogenesis
- Source :
- Cell stem cell, vol 19, iss 2
- Publication Year :
- 2016
- Publisher :
- eScholarship, University of California, 2016.
-
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.
- Subjects :
- 0301 basic medicine
Adenosine Deaminase
bcr-abl
Fusion Proteins, bcr-abl
Medical and Health Sciences
Mice
hemic and lymphatic diseases
Chronic
Cell Self Renewal
Cancer
Regulation of gene expression
Leukemic
Leukemia
Gene Expression Regulation, Leukemic
Myeloid leukemia
RNA-Binding Proteins
Hematology
Biological Sciences
Cell biology
RNA editing
Neoplastic Stem Cells
Molecular Medicine
Stem cell
Signal Transduction
Biotechnology
Biology
03 medical and health sciences
Rare Diseases
Downregulation and upregulation
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
microRNA
medicine
Genetics
Animals
Base Sequence
Fusion Proteins
Cell Biology
Janus Kinase 2
medicine.disease
Stem Cell Research
MicroRNAs
030104 developmental biology
Gene Expression Regulation
Immunology
BCR-ABL Positive
RNA Editing
Biogenesis
Myelogenous
Developmental Biology
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Cell stem cell, vol 19, iss 2
- Accession number :
- edsair.doi.dedup.....3959f35de561890f64dd896e3040d7ee