Department of Medicine, Division of Hematology and Oncology, University of Pittsburgh, Pittsburgh, PA, USA.
Int J Cancer. 2013 Apr 15;132(8):1741-50. doi: 10.1002/ijc.27851. Epub 2012 Oct 17.
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.
慢性髓性白血病 (CML) 患者对 Bcr-Abl 癌蛋白的酪氨酸激酶抑制剂 (TKI) 反应良好。然而，对这些药物的不耐受和耐药仍然是一个挑战，并且 TKI 无法根除罕见的白血病起始细胞。更好地了解白血病起始细胞存活所必需但对正常造血干细胞可有可无的分子信号，将使白血病治疗受益。CML 中的白血病起始细胞可源自髓样祖细胞，我们曾在正常造血中报告该群体依赖于 RNA 编辑酶腺苷脱氨酶作用于 RNA-1 (ADAR1)。我们现在报告称，在条件性 ADAR1 敲除小鼠模型中，Bcr-Abl 转化的白血病细胞依赖 ADAR1。ADAR1 缺失逆转了白细胞增多和脾肿大，并优先耗尽原始 Lin-Sca+Kit+（LSK）白血病细胞，但不耗尽缺乏白血病癌蛋白的 LSK 细胞。ADAR1 缺失最终使外周白细胞计数正常化，通过 PCR 消除了白血病细胞。这些结果揭示了 ADAR1 在髓样白血病细胞中的新需求，并表明 ADAR1 可能成为 CML 靶向治疗的新分子靶点。
