Homo sapiens Raw sequence reads

Post-transcriptional adenosine-to-inosine (A-to-I) RNA editing mediated by adenosine deaminase acting on RNA1 (ADAR1) promotes cancer progression and therapeutic resistance. However, oncogenic activators of ADAR1 and RNA-editing dependent mechanisms governing therapy-resistant cancer stem cell (CSC) generation have not been clearly elucidated. Here we show in human blast crisis chronic myeloid leukemia that increased sensitivity to JAK2 signaling and BCR-ABL1 amplification converge on ADAR1 activation. Selective JAK2 and BCR-ABL1 inhibition prevents CSC self-renewal in a humanized BC CML mouse model commensurate with ADAR1 downregulation. While lentiviral ADAR1 induces self-renewal gene expression and impairs biogenesis of stem cell regulatory let-7 microRNAs, an editing defective lentiviral vector, ADAR1E912A, restores let -7 biogenesis. Combined RNA sequencing, qPCR and stromal co-culture data suggest that ADAR1 promotes CSC generation via let-7 pri-microRNA editing and LIN28B upregulation. Also, small molecule tool compound mediated ADAR1 antagonism impairs CSC self-renewal in stromal co-cultures and restores let-7 biogenesis. Thus, ADAR1 editase activation represents a unique therapeutic vulnerability in CSC with active JAK2 signaling