ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia

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

*Autor correspondiente de este trabajo

Resultado de la investigación: Contribución a una revistaArtículorevisión exhaustiva

121 Citas (Scopus)

Resumen

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, wholetranscriptome 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.

Idioma originalInglés
Páginas (desde-hasta)1041-1046
Número de páginas6
PublicaciónProceedings of the National Academy of Sciences of the United States of America
Volumen110
N.º3
DOI
EstadoPublicada - 15 ene. 2013
Publicado de forma externa

Palabras clave

  • Adenosine Deaminase
  • Alternative Splicing
  • Animals
  • Blast Crisis
  • Cell Transformation
  • Neoplastic
  • Disease Progression
  • Fusion Proteins
  • bcr-abl
  • Gene Knockdown Techniques
  • Glycogen Synthase Kinase 3
  • Humans
  • Inflammation Mediators
  • Leukemia
  • Myelogenous
  • Chronic
  • BCR-ABL Positive
  • Myeloid
  • Chronic-Phase
  • Mice
  • Neoplastic Stem Cells
  • RNA Editing
  • Transcriptome
  • Transplantation
  • Heterologous
  • Tumor Stem Cell Assay

Huella

Profundice en los temas de investigación de 'ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia'. En conjunto forman una huella única.

Citar esto