核心结合因子融合下调ADAR2 RNA编辑有助于造成AML白血病发生。
Core binding factor fusion downregulation of ADAR2 RNA editing contributes to AML leukemogenesis.
发表日期：2023 Feb 16
作者：
Mingrui Guo, Hon Man Tim Chan, Qi-Ling Zhou, Omer An, Ying Li, Yangyang Song, Zi Hui Tan, Hui En Vanessa Ng, Philomina Sona Peramangalam, Zhi Qing Tan, Xinang Cao, Eisaku Iwanaga, Masao Matsuoka, Melissa G Ooi, Wei Ying Jen, Liang Piu Koh, Esther Chan, Lip Kun Tan, Yufen Goh, Wilson Wang, Bryan T H Koh, Ming Chun Chan, Melissa J Fullwood, Wee Joo Chng, Motomi Osato, John Anto Pulikkan, Henry Yang, Leilei Chen, Daniel G Tenen
来源：
BLOOD
摘要：
腺苷转换为肌醇（A-to-I）RNA编辑在肿瘤中发挥贡献，由腺苷酸脱氨酶作用于RNA（ADAR）家族酶ADAR1和ADAR2催化。然而，除慢性髓性白血病（CML）爆发危机外，其他血液恶性肿瘤中其角色的了解相对较少。在这里，我们发现ADAR2在t（8；21）或inv（16）易位基因的核心结合因子（CBF）AML中被明确地下调，而ADAR1和ADAR3则没有。在t（8；21）AML中，RUNX1驱动的ADAR2转录受到RUNX1-ETO AE9a融合蛋白的优势负调控。进一步的功能研究证实，ADAR2能够特异性地抑制t（8；21）和inv16 AML细胞的白血病发生，依赖于其RNA编辑能力。两个典型的ADAR2调节RNA编辑靶COPA和COG3的表达抑制了人t（8；21）AML细胞的克隆增殖。我们的发现支持到目前为止未被认识的机制，导致CBF AML中ADAR2失调，并凸显ADAR2介导的RNA编辑损失与CBF AML的功能相关性。版权所有©2023美国血液学会。
Adenosine to inosine (A-to-I) RNA editing, which is catalyzed by adenosine deaminases acting on RNA (ADAR) family of enzymes ADAR1 and ADAR2, has been shown to contribute to multiple cancers. However, other than chronic myeloid leukemia (CML) blast crisis, relatively little is known about its role in other types of hematological malignancies. Here, we found that ADAR2, but not ADAR1 and ADAR3, was specifically downregulated in the core binding factor (CBF) AML with t(8;21) or inv(16) translocations. In t(8;21) AML, RUNX1-driven transcription of ADAR2 was repressed by the RUNX1-ETO AE9a fusion protein in a dominant negative manner. Further functional studies confirmed that ADAR2 could suppress leukemogenesis specifically in t(8;21) and inv16 AML cells dependent on its RNA editing capability. Expression of two exemplary ADAR2-regulated RNA editing targets COPA and COG3 inhibited clonogenic growth of human t(8;21) AML cells. Our findings support a hitherto unappreciated mechanism leading to ADAR2 dysregulation in CBF AML and highlight the functional relevance of loss of ADAR2-mediated RNA editing to CBF AML.Copyright © 2023 American Society of Hematology.