title: ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia.
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.
authors.affiliation: Stem Cell Program, Department of Medicine, Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Qingfei
authors.initials: Q
authors.lastname: Jiang
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Crews
authors.forename: Christian L
authors.initials: CL
authors.lastname: Barrett
authors.forename: Hye-Jung
authors.initials: HJ
authors.lastname: Chun
authors.forename: Angela C
authors.initials: AC
authors.lastname: Court
authors.forename: Jane M
authors.initials: JM
authors.lastname: Isquith
authors.forename: Maria A
authors.initials: MA
authors.lastname: Zipeto
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Goff
authors.forename: Mark
authors.initials: M
authors.lastname: Minden
authors.forename: Anil
authors.initials: A
authors.lastname: Sadarangani
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Rusert
authors.forename: Kim-Hien T
authors.initials: KH
authors.lastname: Dao
authors.forename: Sheldon R
authors.initials: SR
authors.lastname: Morris
authors.forename: Lawrence S B
authors.initials: LS
authors.lastname: Goldstein
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Frazer
authors.forename: Catriona H M
authors.initials: CH
authors.lastname: Jamieson
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism*; D017398:Alternative Splicing; D000818:Animals; D001752:Blast Crisis / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D018450:Disease Progression; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015466:Leukemia, Myeloid, Chronic-Phase / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D017393:RNA Editing; D016601:RNA-Binding Proteins; D059467:Transcriptome; D014183:Transplantation, Heterologous; D014410:Tumor Stem Cell Assay
chemical_list: D018836:Inflammation Mediators; D016601:RNA-Binding Proteins; D016044:Fusion Proteins, bcr-abl; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase