Article

Abstract 247: ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia.

Stem Cell Program, Department of Medicine, Moores Cancer Center, Division of Genome Information Sciences, Department of Pediatrics, Department of Cellular and Molecular Medicine, and Howard Hughes Medical Institute, University of California at San Diego, La Jolla, CA 92093.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 12/2012; 73(8 Supplement). DOI: 10.1073/pnas.1213021110
Source: PubMed

ABSTRACT

The molecular etiology of human progenitor reprogramming into self-renewing leukemia stem cells (LSC) has remained elusive. Although DNA sequencing has uncovered spliceosome gene mutations that promote alternative splicing and portend leukemic transformation, isoform diversity also may be generated by RNA editing mediated by adenosine deaminase acting on RNA (ADAR) enzymes that regulate stem cell maintenance. In this study, whole-transcriptome sequencing of normal, chronic phase, and serially transplantable blast crisis chronic myeloid leukemia (CML) progenitors revealed increased IFN-γ pathway gene expression in concert with BCR-ABL amplification, enhanced expression of the IFN-responsive ADAR1 p150 isoform, and a propensity for increased adenosine-to-inosine RNA editing during CML progression. Lentiviral overexpression experiments demonstrate that ADAR1 p150 promotes expression of the myeloid transcription factor PU.1 and induces malignant reprogramming of myeloid progenitors. Moreover, enforced ADAR1 p150 expression was associated with production of a misspliced form of GSK3β implicated in LSC self-renewal. Finally, functional serial transplantation and shRNA studies demonstrate that ADAR1 knockdown impaired in vivo self-renewal capacity of blast crisis CML progenitors. Together these data provide a compelling rationale for developing ADAR1-based LSC detection and eradication strategies.

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Available from: Sheldon Robert Morris, Nov 12, 2015
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    • "For example, in brain cancer, editing inhibits cell growth and is reduced in glioma (Maas et al., 2001; Paz et al., 2007) and pediatric astrocytoma (Cenci et al., 2008). In contrast, A-to-I editing increases during chronic myeloid leukemia progression (Jiang et al., 2013). In hepatocellular carcinoma, A-to-I editing of the antizyme inhibitor 1 (AZIN1) increases and neutralizes a key inhibitor of the polyamine synthesis pathway, thereby promoting proliferation in vitro and increasing tumor initiation and volume in a mouse xenograft model (Chen et al., 2013). "
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    ABSTRACT: Little is known about how RNA editing operates in cancer. Transcriptome analysis of 68 normal and cancerous breast tissues revealed that the editing enzyme ADAR acts uniformly, on the same loci, across tissues. In controlled ADAR expression experiments, the editing frequency increased at all loci with ADAR expression levels according to the logistic model. Loci-specific “editabilities,” i.e., propensities to be edited by ADAR, were quantifiable by fitting the logistic function to dose-response data. The editing frequency was increased in tumor cells in comparison to normal controls. Type I interferon response and ADAR DNA copy number together explained 53% of ADAR expression variance in breast cancers. ADAR silencing using small hairpin RNA lentivirus transduction in breast cancer cell lines led to less cell proliferation and more apoptosis. A-to-I editing is a pervasive, yet reproducible, source of variation that is globally controlled by 1q amplification and inflammation, both of which are highly prevalent among human cancers.
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    • "Recent whole genome and transcriptome sequencing studies of hundreds of prostate tumors have defined novel molecular subtypes and characterized extensive genomic aberration underlying disease initiation and progression [15], [16], [17]. RNA editing deregulation has begun to be linked to cancer, including in hepatocellular carcinoma, where recurrent editing of AZIN1 promotes pathogenesis [8], [18], [19]. However, there have been no reports to date in prostate cancer. "
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    ABSTRACT: RNA editing modifies the sequence of primary transcripts, potentially resulting in profound effects to RNA structure and protein-coding sequence. Recent analyses of RNA sequence data are beginning to provide insights into the distribution of RNA editing across the entire transcriptome, but there are few published matched whole genome and transcriptome sequence datasets, and designing accurate bioinformatics methodology has proven highly challenging. To further characterize the RNA editome, we analyzed 16 paired DNA-RNA sequence libraries from prostate tumor specimens, employing a comprehensive strategy to rescue low coverage sites and minimize false positives. We identified over a hundred thousand putative RNA editing events, a third of which were recurrent in two or more samples, and systematically characterized their type and distribution across the genome. Within genes the majority of events affect non-coding regions such as introns and untranslated regions (UTRs), but 546 genes had RNA editing events predicted to result in deleterious amino acid alterations. Finally, we report a potential association between RNA editing of microRNA binding sites within 3' UTRs and increased transcript expression. These results provide a systematic characterization of the landscape of RNA editing in low coverage sequence data from prostate tumor specimens. We demonstrate further evidence for RNA editing as an important regulatory mechanism and suggest that the RNA editome should be further studied in cancer.
    Full-text · Article · Jul 2014 · PLoS ONE
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    • "Aberrant regulation of ADAR-mediated editing of coding and noncoding RNA has been associated with many types of cancer. In addition to those discussed in this review, breast cancer, bladder cancer, prostate cancer, neuroblastoma, Kaposi’s sarcoma, acute leukemia, metastatic melanoma and chronic myeloid leukemia have all been studied in connection with A-to-I RNA editing [25,60,61]. The role of ADARs in carcinogenesis was recently reviewed by Galeano et al.[25]. "
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    ABSTRACT: A-to-I RNA editing is a post-transcriptional modification that converts adenosines to inosines in both coding and noncoding RNA transcripts. It is catalyzed by ADAR (adenosine deaminase acting on RNA) enzymes, which exist throughout the body but are most prevalent in the central nervous system. Inosines exhibit properties that are most similar to those of guanosines. As a result, ADAR-mediated editing can post-transcriptionally alter codons, introduce or remove splice sites, or affect the base pairing of the RNA molecule with itself or with other RNAs. A-to-I editing is a mechanism that regulates and diversifies the transcriptome, but the full biological significance of ADARs is not understood. ADARs are highly conserved across vertebrates and are essential for normal development in mammals. Aberrant ADAR activity has been associated with a wide range of human diseases, including cancer, neurological disorders, metabolic diseases, viral infections and autoimmune disorders. ADARs have been shown to contribute to disease pathologies by editing of glutamate receptors, editing of serotonin receptors, mutations in ADAR genes, and by other mechanisms, including recently identified regulatory roles in microRNA processing. Advances in research into many of these diseases may depend on an improved understanding of the biological functions of ADARs. Here, we review recent studies investigating connections between ADAR-mediated RNA editing and human diseases.
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