Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA.
Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA.
Cancer Cell. 2019 Jan 14;35(1):81-94.e7. doi: 10.1016/j.ccell.2018.11.017. Epub 2019 Jan 3.
Adenosine deaminase associated with RNA1 (ADAR1) deregulation contributes to therapeutic resistance in many malignancies. Here we show that ADAR1-induced hyper-editing in normal human hematopoietic progenitors impairs miR-26a maturation, which represses CDKN1A expression indirectly via EZH2, thereby accelerating cell-cycle transit. However, in blast crisis chronic myeloid leukemia progenitors, loss of EZH2 expression and increased CDKN1A oppose cell-cycle transit. Moreover, A-to-I editing of both the MDM2 regulatory microRNA and its binding site within the 3' UTR region stabilizes MDM2 transcripts, thereby enhancing blast crisis progenitor propagation. These data reveal a dual mechanism governing malignant transformation of progenitors that is predicated on hyper-editing of cell-cycle-regulatory miRNAs and the 3' UTR binding site of tumor suppressor miRNAs.
腺嘌呤脱氨酶与 RNA1（ADAR1）的失调与许多恶性肿瘤的治疗耐药性有关。在这里，我们表明 ADAR1 诱导的正常人类造血祖细胞中的高编辑会损害 miR-26a 的成熟，从而通过 EZH2 间接抑制 CDKN1A 的表达，从而加速细胞周期的过渡。然而，在急变期慢性髓性白血病祖细胞中，EZH2 表达的缺失和 CDKN1A 的增加会阻碍细胞周期的过渡。此外，MDM2 调节 microRNA 的 A 到 I 编辑及其在 3'UTR 区域内的结合位点稳定了 MDM2 转录本，从而增强了急变期祖细胞的增殖。这些数据揭示了一种双重机制，即通过细胞周期调节 microRNA 的高编辑和肿瘤抑制 microRNA 的 3'UTR 结合位点来控制祖细胞的恶性转化。
