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ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia.

Authors
  • Q, Jiang
  • La, Crews
  • Christian Barrett
  • Hj, Chun
  • Ac, Court
  • Jm, Isquith
  • Ma, Zipeto
  • Dj, Goff
  • M, Minden
  • A, Sadarangani
  • Jm, Rusert
  • Kh, Dao
  • Sr, Morris
  • Ls, Goldstein
  • Ma, Marra
  • Kelly A. Frazer
  • Ch, Jamieson
Type
Published Article
Journal
Proceedings of the National Academy of Sciences
Publisher
Proceedings of the National Academy of Sciences
Volume
110
Issue
3
Pages
1041–1046
Identifiers
DOI: 10.1073/pnas.1213021110
Source
Frazer Lab
License
Unknown

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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