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Acute myeloid leukemia

ADAR1 is required for acute myeloid leukemia cell survival by modulating post-transcriptional Wnt signaling through impairing miRNA biogenesis

Leukemia volume 39, pages 599–613 (2025)Cite this article

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Abstract

Recent extensive studies on the genomic and molecular profiles of acute myeloid leukemia (AML) have expanded the treatment options, including, a range of compounds represented by fms-like tyrosine kinase 3 and isocitrate dehydrogenase 1/2 inhibitors. However, despite this progress, further treatments for AML are still required. Adenosine deaminase acting on RNA 1 (ADAR1) has been shown to play an important oncogenic role in many cancers, but its involvement in AML progression remains underexplored. In this study, we demonstrated that ADAR1 was overexpressed in AML and served as a crucial oncogenic target. Loss of ADAR1 inhibited the Wnt signaling pathway, blocked AML cell proliferation, and induced apoptosis. Importantly, we demonstrate that ADAR1, as an RNA-binding protein, interacts with pri-miR-766 independently of its editing function, regulating the maturation of miR-766-3p and enhancing the expression of WNT5B. Genetic inhibition or use of the ADAR1 inhibitor ZYS-1 significantly suppressed AML cell growth both in vitro and in vivo. Overall, these results elucidated the tumorigenic mechanism of ADAR1 and validated it as a potential drug target in AML.

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Fig. 1: ADAR1 is highly expressed in AML and associated with patient prognosis.
Fig. 2: ADAR1 deficiency inhibits AML cell proliferation, induces cell cycle arrest, and promotes apoptosis.
Fig. 3: Transcriptomic sequencing assays to identify ADAR1 regulated WNT signaling pathway via post-transcriptional.
Fig. 4: miR-766-3p is a downstream effector of ADAR1 in regulating WNT5B expression in AML cells.
Fig. 5: ADAR1 inhibits miR-766-3p maturation by binding to pri-miR-766 in an editing-independent manner.
Fig. 6: The ADAR1 inhibitor ZYS-1 suppresses AML cell proliferation both in vitro and in vivo.
Fig. 7: A proposed working model showing the ADAR1/miR-766-3p/WNT5B signaling axis and its roles in contributing to AML proliferation.

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Data availability

The raw sequence data (GSA-Human: HRA008848) reported in this paper have been deposited in the Genome Sequence Archive in National Genomics Data Center, China National Center for Bioinformation / Beijing Institute of Genomics, Chinese Academy of Sciences that are publicly accessible at https://ngdc.cncb.ac.cn/gsa-human. All data generated during this study are included in this published article and its supplementary files. The AML data from the TCGA platform analyzed in this study are available at https://portal.gdc.cancer.gov/. The 70 normal tissue data from GTEx analyzed in his study are available at https://www.gtexportal.org. Source data from GSE34577 and GSE24395 analyzed in this study are available at https://www.ncbi.nlm.nih.gov/geo/. Data for miRNA analysis were obtained from sites TargetScan (https://www.targetscan.org/vert_80/) and miRDB (https://mirdb.org/).

Code availability

No custom code was created in this study.

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Acknowledgements

This study was supported by the National Key R&D Program of China (2022YFA1303803), National Natural Science Foundation of China (82373738, 82321005, 82304296), and the Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University (SKLNMZZ2024JS05). The present study was also supported by Natural Science Foundation of Jiangsu Province (BK20240013, BK20231013), Jiangsu Funding Program for Excellent Postdoctoral Talent (2023ZB125), The Fundamental Research Funds for the Central Universities (2632024ZD06, 2632023GR22). Some images in this article were created using BioRender.com.

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Author notes

  1. These authors contributed equally: Zhongrui Shi, Jiaxing Li, Jiayu Ding, Yiwen Zhang.

Authors and Affiliations

  1. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China

    Zhongrui Shi, Jiaxing Li, Jiayu Ding, Yiwen Zhang, Wenjian Min, Yasheng Zhu, Yi Hou, Kai Yuan, Chengliang Sun, Xuejiao Wang, Hao Shen, Liping Wang, Wenbin Kuang, Xiao Wang & Peng Yang

  2. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China

    Zhongrui Shi, Jiaxing Li, Jiayu Ding, Yiwen Zhang, Wenjian Min, Yasheng Zhu, Yi Hou, Kai Yuan, Chengliang Sun, Xuejiao Wang, Hao Shen, Liping Wang, Wenbin Kuang, Xiao Wang & Peng Yang

  3. Department of Medicine, University of Minnesota Twin Cities, Minneapolis, MN, USA

    Shun-Qing Liang

  4. Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing, China

    Xiao Wang & Peng Yang

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Contributions

PY and XW conceived the study. XW, Z-RS, and J-XL designed the research. Z-RS and J-XL performed most of the experiments with the help of J-YD, Y-WZ, W-JM, Y-SZ, YH, KY, C-LS, X-JW, HS, and L-PW. J-YD and Y-WZ conducted the bioinformatics analysis. All the authors analyzed the data. Z-RS, J-XL, J-YD, and XW wrote the manuscript, while PY, XW, W-BK, and S-QL reviewed and revised it. PY, XW, and W-BK supervised the study.

Corresponding authors

Correspondence to Shun-Qing Liang, Wenbin Kuang, Xiao Wang or Peng Yang.

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Shi, Z., Li, J., Ding, J. et al. ADAR1 is required for acute myeloid leukemia cell survival by modulating post-transcriptional Wnt signaling through impairing miRNA biogenesis. Leukemia 39, 599–613 (2025). https://doi.org/10.1038/s41375-024-02500-7

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