Core-binding factor fusion downregulation of ADAR2 RNA editing contributes to AML leukemogenesis

• Main Authors: Guo, Mingrui, Chan, Tim Hon Man, Zhou, Qiling, An, Omer, Li, Ying, Song, Yangyang, Tan, Zi Hui, Ng, Vanessa Hui En, Peramangalam, Philomina Sona, Tan, Zhi Qing, Cao, Xinang, Iwanaga, Eisaku, Matsuoka, Masao, Ooi, Melissa G. M., Jen, Wei Ying, Koh, Liang Piu, Chan, Esther, Tan, Lip Kun, Goh, Yufen, Wang, Wilson, Koh, Bryan T. H., Chun, Chan Ming, Fullwood, Melissa Jane, Chng, Wee Joo, Osato, Motomi, Pulikkan, John Anto, Yang, Henry, Chen, Leilei, Tenen, Daniel G.
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2023
• Subjects: Science::Medicine; Science::Biological sciences; Acute Myeloid Leukemia; Core Binding Factor
• Online Access: https://hdl.handle.net/10356/170596
• Institution: Nanyang Technological University

Adenosine-to-inosine 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 the chronic myeloid leukemia 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) acute myeloid leukemia (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 additional exon 9a 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 2 exemplary ADAR2-regulated RNA editing targets coatomer subunit α and component of oligomeric Golgi complex 3 inhibits the 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.