Rossetti C, Picardi E, Ye M, Camilli G, D'Erchia A M, Cucina L, Locatelli F, Fianchi L, Teofili L, Pesole G, Gallo A, Sorrentino R
Department of Biology and Biotechnology 'Charles Darwin', University La Sapienza, Rome, Italy.
Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Bari, Italy.
Leukemia. 2017 Dec;31(12):2824-2832. doi: 10.1038/leu.2017.134. Epub 2017 May 9.
Adenosine deaminases acting on RNA (ADARs) are key proteins for hematopoietic stem cell self-renewal and for survival of differentiating progenitor cells. However, their specific role in myeloid cell maturation has been poorly investigated. Here we show that ADAR1 is present at basal level in the primary myeloid leukemia cells obtained from patients at diagnosis as well as in myeloid U-937 and THP1 cell lines and its expression correlates with the editing levels. Upon phorbol-myristate acetate or Vitamin D3/granulocyte macrophage colony-stimulating factor (GM-CSF)-driven differentiation, both ADAR1 and ADAR2 enzymes are upregulated, with a concomitant global increase of A-to-I RNA editing. ADAR1 silencing caused an editing decrease at specific ADAR1 target genes, without, however, interfering with cell differentiation or with ADAR2 activity. Remarkably, ADAR2 is absent in the undifferentiated cell stage, due to its elimination through the ubiquitin-proteasome pathway, being strongly upregulated at the end of the differentiation process. Of note, peripheral blood monocytes display editing events at the selected targets similar to those found in differentiated cell lines. Taken together, the data indicate that ADAR enzymes play important and distinct roles in myeloid cells.
作用于RNA的腺苷脱氨酶（ADARs）是造血干细胞自我更新以及分化祖细胞存活的关键蛋白。然而，它们在髓系细胞成熟中的具体作用尚未得到充分研究。在此，我们表明ADAR1在诊断时从患者获得的原发性髓系白血病细胞以及髓系U - 937和THP1细胞系中以基础水平存在，并且其表达与编辑水平相关。在佛波醇 - 肉豆蔻酸酯乙酸盐或维生素D3/粒细胞巨噬细胞集落刺激因子（GM - CSF）驱动的分化过程中，ADAR1和ADAR2酶均上调，同时A到I的RNA编辑整体增加。ADAR1沉默导致特定ADAR1靶基因的编辑减少，然而，这并未干扰细胞分化或ADAR2活性。值得注意的是，ADAR2在未分化细胞阶段不存在，因为它通过泛素 - 蛋白酶体途径被清除，在分化过程结束时强烈上调。值得注意的是，外周血单核细胞在选定靶标上显示出与分化细胞系中发现的类似的编辑事件。综上所述，数据表明ADAR酶在髓系细胞中发挥着重要且不同的作用。
