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Deletion of the RNA‐editing enzyme ADAR1 causes regression of established chronic myelogenous leukemia in mice
Author(s) -
Steinman Richard A.,
Yang Qiong,
Gasparetto Maura,
Robinson Lisa J.,
Liu Xiaoping,
Lenzner Diana E.,
Hou Jingzhou,
Smith Clayton,
Wang Qingde
Publication year - 2012
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.27851
Subject(s) - chronic myelogenous leukemia , leukemia , biology , myeloid leukemia , cancer research , haematopoiesis , rna editing , stem cell , myeloid , population , progenitor cell , immunology , rna , medicine , microbiology and biotechnology , genetics , gene , environmental health
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.