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 Dao, Sheldon R. Morris, Lawrence S B Goldstein, Marco A. Marra, Kelly A. Frazer, Catriona H M Jamieson

Research output: Contribution to journalArticle

74 Citations (Scopus)

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, 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.

Original languageEnglish (US)
Pages (from-to)1041-1046
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number3
DOIs
StatePublished - Jan 15 2013

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
RNA Editing
Blast Crisis
Leukemia
Stem Cells
Protein Isoforms
Spliceosomes
Inosine
Adenosine Deaminase
Alternative Splicing
DNA Sequence Analysis
Adenosine
Small Interfering RNA
Transplantation
Maintenance
RNA
Gene Expression
Mutation
Enzymes
Genes

ASJC Scopus subject areas

  • General

Cite this

Jiang, Q., Crews, L. A., Barrett, C. L., Chun, H. J., Court, A. C., Isquith, J. M., ... Jamieson, C. H. M. (2013). ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia. Proceedings of the National Academy of Sciences of the United States of America, 110(3), 1041-1046. https://doi.org/10.1073/pnas.1213021110

ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia. / Jiang, Qingfei; Crews, Leslie A.; Barrett, Christian L.; Chun, Hye Jung; Court, Angela C.; Isquith, Jane M.; Zipeto, Maria A.; Goff, Daniel J.; Minden, Mark; Sadarangani, Anil; Rusert, Jessica M.; Dao, Kim-Hien; Morris, Sheldon R.; Goldstein, Lawrence S B; Marra, Marco A.; Frazer, Kelly A.; Jamieson, Catriona H M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 3, 15.01.2013, p. 1041-1046.

Research output: Contribution to journalArticle

Jiang, Q, Crews, LA, Barrett, CL, Chun, HJ, Court, AC, Isquith, JM, Zipeto, MA, Goff, DJ, Minden, M, Sadarangani, A, Rusert, JM, Dao, K-H, Morris, SR, Goldstein, LSB, Marra, MA, Frazer, KA & Jamieson, CHM 2013, 'ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia', Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 3, pp. 1041-1046. https://doi.org/10.1073/pnas.1213021110
Jiang, Qingfei ; Crews, Leslie A. ; Barrett, Christian L. ; Chun, Hye Jung ; Court, Angela C. ; Isquith, Jane M. ; Zipeto, Maria A. ; Goff, Daniel J. ; Minden, Mark ; Sadarangani, Anil ; Rusert, Jessica M. ; Dao, Kim-Hien ; Morris, Sheldon R. ; Goldstein, Lawrence S B ; Marra, Marco A. ; Frazer, Kelly A. ; Jamieson, Catriona H M. / ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 3. pp. 1041-1046.
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