Abstract
Wilms’ tumor 1-associated protein (WTAP) is a key N6-methyladenosine (m6A) methyltransferase that is upregulated in t(8;21) acute myeloid leukemia (AML) under hypoxia inducible factor 1α-mediated transcriptional activation, promoting leukemogenesis through transcriptome-wide m6A modifications. However, the specific substrates and intrinsic regulatory mechanisms of WTAP are not well understood. Here, we provide evidence that PHD finger protein 19 (PHF19) overexpression is regulated by WTAP-mediated m6A modification and promotes cell cycle progression by altering chromatin accessibility. At the same time, high expression of PHF19 and WTAP in t(8;21) AML patients indicates a worse prognosis. Furthermore, inhibition of PHF19 expression significantly suppresses the growth of t(8;21) AML cells in both in vitro and in vivo. Mechanistically, WTAP enhances the stability of PHF19 mRNA by binding to m6A sites in the 3’-untranslated region, thereby upregulating PHF19 expression. Conversely, WTAP suppression reduces m6A modification levels on the PHF19 transcript, leading to increased instability. Knockdown of PHF19 precipitates loss of H3K27 trimethylation and enhanced chromatin accessibility, ultimately resulting in upregulated expression of genes involved in the cell cycle and DNA damage checkpoints. Therefore, WTAP/m6A-dependent PHF19 upregulation accelerates leukemia progression by coordinating m6A modification and histone methylation, establishing its status as a novel therapeutic target for t(8;21) AML.
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Data availability
The raw data generated in this study are publicly available in Gene Expression Omnibus (GEO) at GSE254526, GSE254527 and GSE254528.
References
Khoury JD, Solary E, Abla O, Akkari Y, Alaggio R, Apperley JF, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022;36:1703–19.
Döhner H, Wei AH, Appelbaum FR, Craddock C, DiNardo CD, Dombret H, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022;140:1345–77.
Han SY, Mrózek K, Voutsinas J, Wu Q, Morgan EA, Vestergaard H, et al. Secondary cytogenetic abnormalities in core-binding factor AML harboring inv(16) vs t(8;21). Blood Adv. 2021;5:2481–9.
Christen F, Hoyer K, Yoshida K, Hou HA, Waldhueter N, Heuser M, et al. Genomic landscape and clonal evolution of acute myeloid leukemia with t(8;21): an international study on 331 patients. Blood. 2019;133:1140–51.
Rejeski K, Duque-Afonso J, Lübbert M. AML1/ETO and its function as a regulator of gene transcription via epigenetic mechanisms. Oncogene. 2021;40:5665–76.
Gao XN, Yan F, Lin J, Gao L, Lu XL, Wei SC, et al. AML1/ETO cooperates with HIF1α to promote leukemogenesis through DNMT3a transactivation. Leukemia. 2015;29:1730–40.
An Y, Duan H. The role of m6A RNA methylation in cancer metabolism. Mol Cancer. 2022;21:14.
Yang Y, Hsu PJ, Chen YS, Yang YG. Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism. Cell Res. 2018;28:616–24.
Ping XL, Sun BF, Wang L, Xiao W, Yang X, Wang WJ, et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 2014;24:177–89.
Ju G, Lei J, Cai S, Liu S, Yin X, Peng C. The Emerging, Multifaceted Role of WTAP in Cancer and Cancer Therapeutics. Cancers. 2023;15:3053.
Shao YL, Li YQ, Li MY, Wang LL, Zhou HS, Liu DH, et al. HIF1α-mediated transactivation of WTAP promotes AML cell proliferation via m6A-dependent stabilization of KDM4B mRNA. Leukemia. 2023;37:1254–67.
Chen Z, Shao YL, Wang LL, Lin J, Zhang JB, Ding Y, et al. YTHDF2 is a potential target of AML1/ETO-HIF1α loop-mediated cell proliferation in t(8;21) AML. Oncogene. 2021;40:3786–98.
de Jonge HJ, Valk PJ, Veeger NJ, ter Elst A, den Boer ML, Cloos J, et al. High VEGFC expression is associated with unique gene expression profiles and predicts adverse prognosis in pediatric and adult acute myeloid leukemia. Blood. 2010;116:1747–54.
Kharas MG, Lengner CJ, Al-Shahrour F, Bullinger L, Ball B, Zaidi S, et al. Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia. Nat Med. 2010;16:903–8.
Ballaré C, Lange M, Lapinaite A, Martin GM, Morey L, Pascual G, et al. Phf19 links methylated Lys36 of histone H3 to regulation of Polycomb activity. Nat Struct Mol Biol. 2012;19:1257–65.
Wang HH, Lee YN, Su CH, Shu KT, Liu WT, Hsieh CL, et al. S-Phase Kinase-associated Protein-2 Rejuvenates Senescent Endothelial Progenitor Cells and Induces Angiogenesis in Vivo. Sci Rep. 2020;10:6646.
Hunkapiller J, Shen Y, Diaz A, Cagney G, McCleary D, Ramalho-Santos M, et al. Polycomb-like 3 promotes polycomb repressive complex 2 binding to CpG islands and embryonic stem cell self-renewal. PLoS Genet. 2012;8:e1002576.
Brien GL, Gambero G, O’Connell DJ, Jerman E, Turner SA, Egan CM, et al. Polycomb PHF19 binds H3K36me3 and recruits PRC2 and demethylase NO66 to embryonic stem cell genes during differentiation. Nat Struct Mol Biol. 2012;19:1273–81.
Deng Q, Hou J, Feng L, Lv A, Ke X, Liang H, et al. PHF19 promotes the proliferation, migration, and chemosensitivity of glioblastoma to doxorubicin through modulation of the SIAH1/β-catenin axis. Cell Death Dis. 2018;9:1049.
Zhu ZY, Tang N, Wang MF, Zhou JC, Wang JL, Ren HZ, et al. Comprehensive Pan-Cancer Genomic Analysis Reveals PHF19 as a Carcinogenic Indicator Related to Immune Infiltration and Prognosis of Hepatocellular Carcinoma. Front Immunol. 2022;12:781087.
Jain P, Ballare C, Blanco E, Vizan P, Di Croce L. PHF19 mediated regulation of proliferation and invasiveness in prostate cancer cells. Elife. 2020;9:e51373.
Ghislin S, Deshayes F, Middendorp S, Boggetto N, Alcaide-Loridan C. PHF19 and Akt control the switch between proliferative and invasive states in melanoma. Cell Cycle. 2012;11:1634–45.
GarcÃa-Montolio M, Ballaré C, Blanco E, Gutiérrez A, Aranda S, Gómez A, et al. Polycomb Factor PHF19 Controls Cell Growth and Differentiation Toward Erythroid Pathway in Chronic Myeloid Leukemia Cells. Front Cell Dev Biol. 2021;9:655201.
Vizán P, Gutiérrez A, Espejo I, GarcÃa-Montolio M, Lange M, Carretero A, et al. The Polycomb-associated factor PHF19 controls hematopoietic stem cell state and differentiation. Sci Adv. 2020;6:eabb2745.
Ren Z, Ahn JH, Liu H, Tsai YH, Bhanu NV, Koss B. PHF19 promotes multiple myeloma tumorigenicity through PRC2 activation and broad H3K27me3 ___domain formation. Blood. 2019;134:1176–89.
Li Y, Gao L, Luo X, Wang L, Gao X, Wang W, et al. Epigenetic silencing of microRNA-193a contributes to leukemogenesis in t(8;21) acute myeloid leukemia by activating the PTEN/PI3K signal pathway. Blood. 2013;121:499–509.
Ratnadiwakara M, Änkö ML. mRNA Stability Assay Using transcription inhibition by Actinomycin D in Mouse Pluripotent Stem Cells. Bio Protoc. 2018;8:e3072.
Acknowledgements
We acknowledge Prof. Yuheng Shi from Fudan University for providing bone marrow cells of mouse AML model. The study was supported by grants from National Natural Science Foundation of China (No. 82470158, 82070149, 81870109, 82122004, 82070104), National Key R&D Program of China (2020YFA0112401) and the Natural Science Foundation of Beijing Municipality (7202191).
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XNG conceived ideas, designed the experiments; YQL, LLW, YLS, HSZ, YLH, and KLM performed the experiments; YQL and JL carried out statistical analysis and interpreted data; JZ and DL performed ATAC-seq and RNA-seq data processing and analysis; XNG and JL wrote the paper; JZ, CJG and DHL critically reviewed the paper. All authors vouch for the completeness and accuracy of the data and analysis.
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Human samples were obtained from AML patients and healthy donors after signed informed consent were obtained. The experiments adhered to established ethical standards and the Declaration of Helsinki, and were approved by the Human Subject Ethics Committee in Chinese PLA General Hospital (Approval No.KY-2022-4-19-1). All animal experiments were performed with the approval of the Chinese PLA General Hospital Animal Care and Use Committee and conducted according to guiding principles for research involving animals (Approval No. SQ2021212).
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Li, YQ., Liu, D., Wang, LL. et al. WTAP-mediated m6A methylation of PHF19 facilitates cell cycle progression by remodeling the accessible chromatin landscape in t(8;21) AML. Oncogene 44, 1504–1516 (2025). https://doi.org/10.1038/s41388-025-03329-9
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DOI: https://doi.org/10.1038/s41388-025-03329-9
