title: Deletion of the RNA-editing enzyme ADAR1 causes regression of established chronic myelogenous leukemia in mice.
abstract: Patients with chronic myelogenous leukemia (CML) respond well to tyrosine kinase inhibitors (TKIs) of the Bcr-Abl oncoprotein. However, intolerance and resistance to these agents remains a challenge, and TKIs are unable to eradicate rare leukemia-initiating cells. Leukemia treatment would benefit from a better understanding of molecular signals that are necessary for the survival of leukemia-initiating cells but dispensable for normal hematopoietic stem cells. Leukemia-initiating cells in CML can arise from myeloid progenitor cells, a population that we have reported in normal hematopoiesis to depend on the RNA-editing enzyme adenosine deaminase acting on RNA-1 (ADAR1). We now report that Bcr-Abl transformed leukemic cells were ADAR1-dependent in a conditional ADAR1 knockout mouse model. ADAR1 deletion reversed leukocytosis and splenomegaly, and preferentially depleted primitive Lin-Sca+Kit+ (LSK) leukemic cells but not LSK cells lacking the leukemic oncoprotein. ADAR1 deletion ultimately normalized the peripheral white blood count, eliminating leukemic cells as assessed by PCR. These results uncover a novel requirement for ADAR1 in myeloid leukemic cells and indicate that ADAR1 may comprise a new molecular target for CML-directed therapeutics.
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, University of Pittsburgh, Pittsburgh, PA, USA. steinman@pitt.edu
authors.forename: Richard A
authors.initials: RA
authors.lastname: Steinman
authors.forename: Qiong
authors.initials: Q
authors.lastname: Yang
authors.forename: Maura
authors.initials: M
authors.lastname: Gasparetto
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Robinson
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Liu
authors.forename: Diana E
authors.initials: DE
authors.lastname: Lenzner
authors.forename: Jingzhou
authors.initials: J
authors.lastname: Hou
authors.forename: Clayton
authors.initials: C
authors.lastname: Smith
authors.forename: Qingde
authors.initials: Q
authors.lastname: Wang
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics*; D058892:Adenosine Deaminase Inhibitors / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors; D017353:Gene Deletion; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D058892:Adenosine Deaminase Inhibitors; D017931:DNA Primers; D013629:Tamoxifen; D016044:Fusion Proteins, bcr-abl; D000243:Adenosine Deaminase