Cancer Science Institute of Singapore, National University of Singapore, Singapore.
Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Blood. 2023 Jun 22;141(25):3078-3090. doi: 10.1182/blood.2022015830.
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.
腺嘌呤核苷到肌苷核苷 RNA 编辑，由腺嘌呤脱氨酶作用于 RNA（ADAR）家族的酶，ADAR1 和 ADAR2 催化，已被证明有助于多种癌症。然而，除了慢性髓性白血病急变期外，人们对其在其他类型血液恶性肿瘤中的作用知之甚少。在这里，我们发现，在具有 t(8;21)或 inv(16)易位的核心结合因子（CBF）急性髓系白血病（AML）中，ADAR2 而非 ADAR1 和 ADAR3 特异性下调。在 t(8;21)AML 中，RUNX1-ETO 额外外显子 9a 融合蛋白以显性负性方式抑制 ADAR2 的 RUNX1 驱动转录。进一步的功能研究证实，ADAR2 可以通过其 RNA 编辑能力特异性抑制 t(8;21)和 inv16 AML 细胞的白血病发生。2 个示例性的 ADAR2 调节的 RNA 编辑靶标衣壳蛋白亚基 α和寡聚高尔基体复合物 3 的表达抑制人 t(8;21)AML 细胞的集落形成生长。我们的研究结果支持了一种迄今为止尚未被认识的机制，导致 CBF AML 中 ADAR2 失调，并强调了 ADAR2 介导的 RNA 编辑缺失对 CBF AML 的功能相关性。
