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

Area of Science:

• Molecular Biology
• Cancer Research
• Hematology

Background:

• Post-transcriptional RNA editing by ADAR1 is implicated in cancer progression and resistance.
• Mechanisms by which ADAR1 influences leukemia stem cell (LSC) generation remain unclear.

Purpose of the Study:

• To investigate the role of ADAR1 in the generation of LSCs in blast crisis chronic myeloid leukemia (BC CML).
• To explore ADAR1 as a potential therapeutic target in BC CML.

Main Methods:

• Utilized a humanized BC CML mouse model.
• Employed combined JAK2 and BCR-ABL1 inhibition.
• Conducted lentiviral transduction with wild-type and mutant ADAR1.
• Performed RNA sequencing, qRT-PCR, and CLIP-ADAR1 assays.
• Used a small-molecule tool compound targeting ADAR1.

Main Results:

• Increased JAK2 signaling and BCR-ABL1 amplification activate ADAR1 in BC CML.
• Combined JAK2 and BCR-ABL1 inhibition reduced LSC self-renewal and ADAR1 levels.
• ADAR1, but not an editing-defective mutant, promoted LSC self-renewal gene expression and impaired let-7 microRNA biogenesis.
• ADAR1 promotes LSC generation via let-7 pri-microRNA editing and LIN28B upregulation.
• A small-molecule compound inhibited ADAR1's effect on LSC self-renewal and restored let-7 biogenesis.

Conclusions:

• ADAR1 activation is a key driver of LSC generation in BC CML with active JAK2 signaling.
• Targeting ADAR1 represents a promising therapeutic strategy for BC CML.