Journal Article

ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia

Jamieson, Catriona H. M., Dao, Kim-Hien T., Goldstein, Lawrence S. B., Zipeto, Maria A., Sadarangani, Anil, Chun, Hye-Jung, Jiang, Qingfei, Isquith, Jane M., Rusert, Jessica M., Court, Angela C., Goff, Daniel J., Crews, Leslie A., Marra, Marco A., Morris, Sheldon R., Minden, Mark, Frazer, Kelly A., Barrett, Christian L.

2013

Overview

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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: adenosine deaminase / Adenosine Deaminase - genetics / Adenosine Deaminase - metabolism / Alternative Splicing / Animals / Biological Sciences / Blast Crisis - etiology / Blast Crisis - genetics / Blast Crisis - metabolism / Blast Crisis - pathology / Cell Transformation, Neoplastic / Cells / Chronic myeloid leukemia / Cord blood / Disease Progression / Enzymes / etiology / Fusion Proteins, bcr-abl - genetics / Fusion Proteins, bcr-abl - metabolism / Gene expression / Gene Knockdown Techniques / gene overexpression / Genes / Glycogen Synthase Kinase 3 - genetics / Glycogen Synthase Kinase 3 - metabolism / Glycogen Synthase Kinase 3 beta / Humans / Inflammation Mediators - metabolism / interferon-gamma / Leukemia / Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics / Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism / Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology / Leukemia, Myeloid, Chronic-Phase - genetics / Leukemia, Myeloid, Chronic-Phase - metabolism / Leukemia, Myeloid, Chronic-Phase - pathology / Mice / Mutation / myeloid leukemia / Neoplastic Stem Cells - metabolism / Neoplastic Stem Cells - pathology / Progenitor cells / Protein isoforms / Ribonucleic acid / RNA / RNA Editing / RNA-Binding Proteins / sequence analysis / spliceosomes / Stem cells / tau-protein kinase / transcription factors / Transcriptome / Transplantation, Heterologous / Tumor Stem Cell Assay / Up regulation