While advanced malignancies in Chronic Myeoloid Leukemia (CML) are diverse in phenotype, they often exhibit stem cell properties including enhanced survival, quiescence and self-renewal potential. The molecular etiology of human progenitor reprogramming into self-renewing leukemia stem cells (LSC) has remained elusive. While DNA sequencing has uncovered spliceosome gene mutations that promote alternative splicing and portend leukemic transformation, isoform diversity may also be generated by aberrant RNA editing mediated by adenosine deaminase acting on dsRNA (ADAR) family, which have been shown to promote an embryonic transcriptional program and regulate fetal and adult hematopoietic stem cell (HSC) self-renewal as well as stem cell responses to inflammation. In this study, whole transcriptome sequencing of normal, chronic phase (CP) and functionally validated blast crisis (BC) chronic myeloid leukemia (CML) progenitors revealed increased inflammatory pathway gene expression in concert with BCR-ABL amplification, enhanced expression of interferon-responsive ADAR1 and a propensity for increased A-to-I RNA editing during CML progression. Mechanistic studies demonstrated that lentivirally enforced ADAR1 p150 expression induced expression of the myeloid-skewing transcription factor PU.1 and skewed cell fate towards granulocyte-macrophage progenitors - the initiating LSC population in BC CML. Moreover, lentiviral ADAR1 knockdown reduced BC LSC self-renewal capacity in RAG2−/−gc−/− mice. These data shed new light on the role of ADAR1-directed RNA editing in myeloid progenitor reprogramming and self-renewal potential of malignant progenitors that drive disease progression and therapeutic resistance in CML, and provide a compelling rationale for developing ADAR1-based LSC detection and eradication strategies.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.