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 TKI’s 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 ADAR1 (adenosine deaminase acting on RNA-1). 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.

RNA Processing and Ribosome Biogenesis in Bone Marrow Failure Disorders

“…It has been demonstrated that ADAR1 is also involved in chronic myeloid leukemia. Indeed, Wang and collaborators reported that ADAR1 is required for Bcr-Abl leukemia cell survival in vivo and that silencing ADAR1 results in a rapid leukemic cell loss [63] . These studies elegantly uncover the role of ADAR1 in myeloid leukemia cells and indicate ADAR1 as a promising molecular target for CML-directed therapeutic interventions [63] .…”

“…Indeed, Wang and collaborators reported that ADAR1 is required for Bcr-Abl leukemia cell survival in vivo and that silencing ADAR1 results in a rapid leukemic cell loss [63] . These studies elegantly uncover the role of ADAR1 in myeloid leukemia cells and indicate ADAR1 as a promising molecular target for CML-directed therapeutic interventions [63] . While ADAR1 seems to play a major role in disease affecting hematological compartment recently a role for the ADAR2 enzyme has also been recently demonstrated.…”

ADAR1 Prevents Liver Injury from Inflammation and Suppresses Interferon Production in Hepatocytes

“…46,55 Hepatocytes free of nonparenchymal cells were isolated from the inducible ADAR1 KO mice by two-step liver perfusion, and the cells were cultured under 56,57 Tamoxifen was added to the culture medium to induce ADAR1 gene deletion ( Figure 6A). ADAR1 gene deletion was effectively achieved by tamoxifen induction in the hepatocytes, as verified by the PCR analysis of the ADAR1 gene alleles and diminishing levels of ADAR1 protein ( Figure 6, B and C).…”

“…55 Germline deletion of ADAR1 in mice results in embryonic lethality at embryonic 11.5 to 12 days after coitus. 28 Intriguingly, no obvious morphological defects are observed in organs other than the liver, including the placenta, heart, kidneys, brain, and other tissues, despite ADAR1 expression not being confined to the liver.…”

ADAR1: a promising new biomarker for esophageal squamous cell carcinoma?

“…Due to the interferonresponsive ADAR1 activity, ADAR1 p150 was upregulated in chronic myeloid leukemia patient samples, which was correlated with BCR/ABL (oncogenic gene fusion protein) amplification and the increased A-to-I editing level [30]. Similarly, ADAR1 was also found to be required for the survival of leukemia cells [31]. Among different types of pediatric acute leukemias, only the B-cell acute lymphoblastic leukemia subgroup exhibited a significant overexpression of ADAR1 p110, with a dramatic decrease in its level in patients achieving complete remission [32].…”