Deletion of the RNA-editing enzyme ADAR1 causes regression of established chronic myelogenous leukemia in mice

作者：Steinman Richard A; Yang Qiong; Gasparetto Maura; Robinson Lisa J; Liu Xiaoping; Lenzner Diana E; Hou Jingzhou; Smith Clayton; Wang Qingde^*

来源：International Journal of Cancer, 2013, 132(8): 1741-1750.

DOI：10.1002/ijc.27851

• RNA editing
• ADAR1
• CML
• imatinib

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.

• 出版日期2013-4-15