Novel Role of RNA Editing by ADAR2 in Core Binding Factor Acute Myelogenous Leukemias

A team of researchers from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore, co-led by Professor Daniel G. Tenen and Associate Professor Polly Chen Leilei, has for the first time discovered a hitherto unappreciated mechanism leading to ADAR2 (adenosine deaminases acting on RNA) dysregulation in core binding factor acute myelogenous leukemias (CBF-AML) and highlights the functional relevance of the role of ADAR2 role in leukemogenesis, in work just published in the prestigious journal Blood on 16 February 2023.

Adenosine to inosine (A-to-I) RNA editing, catalysed by ADAR family of enzymes ADAR1 and ADAR2, has been shown to contribute to multiple cancers. However, little is known of their roles in hematological malignancies. Here, the team managed to comprehensively profile expression of ADAR expression (ADAR1 – 3) in different subtypes of AML and found that ADAR2, but not ADAR1 and ADAR3, was differentially expressed in CBF-AML patients. CBF-AML is characterized by the presence of either t(8;21) or inv(16) translocations, which affect the RUNX transcription factor heterodimer. In their study, they discovered a previously undescribed regulatory mechanism leading to ADAR2 downregulation in AMLs in which the formation of AML1-ETO fusion gene and its truncated form AE9a halts the transcription of the ADAR2 gene. To further support their hypothesis that loss of ADAR2 and RNA editing may specifically contribute to development of CBF-AML, they re-expressed ADAR2 in CBF-AML and non-CBF-AML and found that leukemogenesis was suppressed in the CBF-AML cells.  In addition, the RNA editing capability of ADAR2 was essential for its suppression of leukemogenesis in an AE9a-driven AML mouse model. These studies revealed for the first time a role of ADAR2-mediated RNA editing in suppressing leukemogenesis.

“The understanding of the role of ADAR2 and ADAR2-mediated RNA editing in cancer has long been neglected, with researchers in this field being more focused on the role of ADAR1 and RNA editing in cancers, including hematological malignancies. Our motivation is to systematically investigate the potential role of ADAR-mediated RNA editing in AML,” said Associate Professor Chen, the co-lead author of this paper and an internationally known expert in the role of RNA editing in cancer.

This work propels the team to delve deeper on the causes and functional consequences of ADAR2 dysregulation in multiple diseases, including cancer, as well as the underlying mechanisms (editing-dependent or independent) leading to pathogenesis. CBF-AML accounts for up to 20% of cases of AML, and while it has a relatively good prognosis, nevertheless approximately half of AML patients will eventually relapse with subsequent poor survival. Therefore, the ability to modulate the level of ADAR2 and editing frequency of its RNA substrates may hold great potential for the development of RNA therapeutics against CBF-AMLs, leading to improved treatment outcomes.

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