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

Abstract

SUMMARY 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 ADAR1E912 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 LSC with active JAK2 signaling.

RNA editing-dependent epitranscriptome diversity in cancer stem cells

“…The resulting inosine bases are subsequently read as guanosines, thus inducing A-to-G post-transcriptional changes that contribute to transcriptome diversity. Although the precise mechanisms governing RNA editing events in cancer are currently the subject of intense investigation, copy number amplification at chromosome 1q 39 — the locus of the human ADAR1 gene — and inflammation 7,40 are two primary mechanisms that may contribute to induction of RNA editing in cancer. Normally, ADAR1 transcription is activated by RNA viruses and represents an essential component of the innate antiviral immune response 41 .…”

RNA Splicing Modulation Selectively Impairs Leukemia Stem Cell Maintenance in Secondary Human AML

“…Recently, pre-mRNA splicing alterations (Abrahamsson et al, 2009; Adamia et al, 2014; DeBoever et al, 2015; Goff et al, 2013; Holm et al, 2015), together with RNA editing and lncRNA deregulation, were associated with therapeutic resistance in leukemia (Crews et al, 2015; Jiang et al, 2013; Trimarchi et al, 2014). With regard to the functional impact of RNA processing alterations on therapeutic resistance, we discovered that malignant reprogramming of human pre-leukemic progenitors into self-renewing LSC was enhanced by missplicing of a stem cell regulatory transcript, GSK3β (Abrahamsson et al, 2009), through RNA editing (Crews et al, 2015; Jiang et al, 2013; Zipeto et al, 2016) and pro-survival BCL2 family splice isoform switching in CML (Goff et al, 2013). Moreover, reversion to an embryonic splicing program by MBNL 3 downregulation also promoted acute leukemic transformation (Holm et al, 2015) and underscored the importance of splicing deregulation in human LSC generation.…”

Functions of the RNA Editing Enzyme ADAR1 and Their Relevance to Human Diseases

“…In chronic myeloid leukemia, the increased expressions of IFN-γ-R1 and IL-3Rα upregulate ADAR1′s transcription through JAK2, which controls the biogenesis of let-7 miRNA and the self-renewal of leukemia stem cells. A-to-I editing by ADAR1 is needed for the transformation into the malignant pathway, by inhibiting let-7 miRNA biogenesis and promoting the self-renewal of progenitor cells [144]. This would also explain the higher ADAR1p150 levels observed with dysregulated levels of the myeloid transcription factor PU.1 and mis-splicing of the GSK3-β protein, which drives the blastic transformation between the second and third phases of disease progression [145].…”