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YTHDF2 is a potential target of AML1/ETO-HIF1α loop-mediated cell proliferation in t(8;21) AML

Oncogene volume 40, pages 3786–3798 (2021)Cite this article

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Abstract

The t(8;21) fusion product, AML1/ETO, and hypoxia-inducible factor 1α (HIF1α) form a feed-forward transcription loop that cooperatively transactivates the DNA methyltransferase 3a gene promoter that leads to DNA hypermethylation and drives leukemia cell growth. Suppression of the RNA N6-methyladenosine (m6A)-reader enzyme YTH N6-methyladenosine RNA binding protein 2 (YTHDF2) specifically compromises cancer stem cells in acute myeloid leukemia (AML) but promotes hematopoietic stem cell expansion without derailing normal hematopoiesis. However, the relevance of expression between AML1/ETO-HIF1α loop and YTHDF2, and its functional relationship with t(8;21) AML have not been documented. Here, we show that YTHDF2 is highly expressed in t(8;21) AML patients and associated with a higher risk of relapse and inferior relapse-free survival. Knockdown of YTHDF2 in leukemia cells causes an impaired cell proliferation rate in vitro and in mice. Mechanistically, HIF1α is able to bind to the hypoxia-response elements of the 5′-untranslated region of the YTHDF2 gene and promotes the transactivity of the YTHDF2 promoter. Knockdown and overexpression of either AML1/ETO or HIF1α resulted in decreased and increased YTHDF2 protein and mRNA expression in t(8;21) AML cells. In particular, knockdown of YTHDF2 resulted in increased global mRNA m6A levels in t(8;21) AML cells, accompanied by increased TNF receptor superfamily member 1b (TNFRSF1b) mRNA and protein expression levels. Last, we demonstrated that the m6A methylation and expression levels of the TNFRSF1b gene were both negatively correlated with HIF1α expression levels. In conclusion, YTHDF2 is a downstream target of the AML1/ETO-HIF1α loop and promotes cell proliferation probably by modulating the global m6A methylation in t(8;21) AML.

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Fig. 1: Selectively high expression of YTHDF2 in t(8;21) AML predicts inferior relapse-free survival.
Fig. 2: Silencing of YTHDF2 expression in t(8;21) AML cell lines led to a decreased colony-forming ability by colony-forming assay.
Fig. 3: HIF1α induces the transcriptional activity of the YTHDF2 promoter through direct promoter binding.
Fig. 4: HIF1α induces YTHDF2 high expression in t(8;21) AML cells.
Fig. 5: AML1/ETO induces YTHDF2 expression.
Fig. 6: Silencing of YTHDF2 increases m6A methylation levels and TNF-R2 expression.
Fig. 7: HIF1α regulates TNFRSF1b expression probably by influencing the m6A mRNA methylation.

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Data availability

The m6A sequencing data have been deposited in Gene Expression Omnibus (GEO) with the accession code GSE168778.

References

  1. Appelbaum FR, Kopecky KJ, Tallman MS, Slovak ML, Gundacker HM, Kim HT, et al. The clinical spectrum of adult acute myeloid leukaemia associated with core binding factor translocations. Br J Haematol. 2006;135:165–73.

    Article  Google Scholar 

  2. Schlenk RF, Benner A, Krauter J, Büchner T, Sauerland C, Ehninger G, et al. Individual patient data-based meta-analysis of patients aged 16 to 60 years with core binding factor acute myeloid leukemia: a survey of the German Acute Myeloid Leukemia Intergroup. J Clin Oncol. 2004;22:3741–50.

    Article  CAS  Google Scholar 

  3. Marcucci G, Mrózek K, Ruppert AS, Maharry K, Kolitz JE, Moore JO, et al. Prognostic factors and outcome of core binding factor acute myeloid leukemia patients with t(8;21) differ from those of patients with inv(16): a Cancer and Leukemia Group B study. J Clin Oncol. 2005;23:5705–17.

    Article  Google Scholar 

  4. Prébet T, Boissel N, Reutenauer S, Thomas X, Delaunay J, Cahn JY, et al. Acute myeloid leukemia with translocation (8;21) or inversion (16) in elderly patients treated with conventional chemotherapy: a collaborative study of the French CBF-AML intergroup. J Clin Oncol. 2009;27:4747–53.

    Article  Google Scholar 

  5. Yan M, Burel SA, Peterson LF, Kanbe E, Iwasaki H, Boyapati A, et al. Deletion of an AML1-ETO C-terminal NcoR/SMRT-interacting region strongly induces leukemia development. Proc Natl Acad Sci USA. 2004;101:17186–91.

    Article  CAS  Google Scholar 

  6. Al-Harbi S, Aljurf M, Mohty M, Almohareb F, Ahmed SOA. An update on the molecular pathogenesis and potential therapeutic targeting of AML with t(8;21)(q22;q22.1); RUNX1-RUNX1T1. Blood Adv. 2020;4:229–38.

    Article  CAS  Google Scholar 

  7. 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.

    Article  CAS  Google Scholar 

  8. Wang X, Zhao BS, Roundtree IA, Lu Z, Han D, Ma H, et al. N(6)-methyladenosine modulates messenger RNA translation efficiency. Cell. 2015;161:1388–99.

    Article  CAS  Google Scholar 

  9. Barbieri I, Tzelepis K, Pandolfini L, Shi J, Millán-Zambrano G, Robson SC, et al. Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control. Nature. 2017;552:126–31.

    Article  CAS  Google Scholar 

  10. Vu LP, Pickering BF, Cheng Y, Zaccara S, Nguyen D, Minuesa G, et al. The N6-methyladenosine (m6A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells. Nat Med. 2017;23:1369–76.

    Article  CAS  Google Scholar 

  11. Weng H, Huang H, Wu H, Qin X, Zhao BS, Dong L, et al. METTL14 inhibits hematopoietic stem/progenitor differentiation and promotes leukemogenesis via mRNA m6A modification. Cell Stem Cell. 2018;22:191–205.

    Article  CAS  Google Scholar 

  12. Li Z, Weng H, Su R, Weng X, Zuo Z, Li C, et al. FTO plays an oncogenic role in acute myeloid leukemia as a n6-methyladenosine RNA demethylase. Cancer Cell. 2017;31:127–41.

    Article  Google Scholar 

  13. Du H, Zhao Y, He J, Zhang Y, Xi H, Liu M, et al. YTHDF2 destabilizes m(6)A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex. Nat Commun. 2016;7:12626.

    Article  CAS  Google Scholar 

  14. Li Z, Qian P, Shao W, Shi H, He XC, Gogol M, et al. Suppression of m6A reader Ythdf2 promotes hematopoietic stem cell expansion. Cell Res. 2018;28:904–17.

    Article  CAS  Google Scholar 

  15. Wang H, Zuo H, Liu J, Wen F, Gao Y, Zhu X, et al. Loss of YTHDF2-mediated m6A-dependent mRNA clearance facilitates hematopoietic stem cell regeneration. Cell Res. 2018;28:1035–8.

    Article  CAS  Google Scholar 

  16. Paris J, Morgan M, Campos J, Spencer GJ, Shmakova A, Ivanova I, et al. Targeting the RNA m6A reader YTHDF2 selectively compromises cancer stem cells in acute myeloid leukemia. Cell Stem Cell. 2019;25:137–48.

    Article  CAS  Google Scholar 

  17. 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.

    Article  Google Scholar 

  18. Valk PJ, Verhaak RG, Beijen MA, Erpelinck CA, Barjesteh van Waalwijk van Doorn-Khosrovani S, Boer JM, et al. Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med. 2004;350:1617–28.

    Article  CAS  Google Scholar 

  19. Su R, Dong L, Li C, Nachtergaele S, Wunderlich M, Qing Y, et al. R-2HG exhibits anti-tumor activity by targeting FTO/m6A/MYC/CEBPA signaling. Cell. 2018;172:90–105.

    Article  CAS  Google Scholar 

  20. Zhong L, Liao D, Zhang M, Zeng C, Li X, Zhang R, et al. YTHDF2 suppresses cell proliferation and growth via destabilizing the EGFR mRNA in hepatocellular carcinoma. Cancer Lett. 2019;442:252–61.

    Article  CAS  Google Scholar 

  21. Hou J, Zhang H, Liu J, Zhao Z, Wang J, Lu Z, et al. YTHDF2 reduction fuels inflammation and vascular abnormalization in hepatocellular carcinoma. Mol Cancer. 2019;18:163.

    Article  Google Scholar 

  22. Sheng H, Li Z, Su S, Sun W, Zhang X, Li L, et al. YTH domain family 2 promotes lung cancer cell growth by facilitating 6-phosphogluconate dehydrogenase mRNA translation. Carcinogenesis. 2020;41:541–50.

    Article  CAS  Google Scholar 

  23. Li J, Meng S, Xu M, Wang S, He L, Xu X. et al. Downregulation of N(6)-methyladenosine binding YTHDF2 protein mediated by miR-493-3p suppresses prostate cancer by elevating N(6)-methyladenosine levels. Oncotarget. 2017;9:3752–64.

    Article  Google Scholar 

  24. Chen J, Sun Y, Xu X, Wang D, He J, Zhou H, et al. YTH domain family 2 orchestrates epithelial-mesenchymal transition/proliferation dichotomy in pancreatic cancer cells. Cell Cycle. 2017;16:2259–71.

    Article  CAS  Google Scholar 

  25. Wang J, Hoshino T, Redner RL, Kajigaya S, Liu JM. ETO, fusion partner in t(8;21) acute myeloid leukemia, represses transcription by interaction with the human N-CoR/mSin3/HDAC1 complex. Proc Natl Acad Sci USA. 1998;95:10860–5.

    Article  CAS  Google Scholar 

  26. Fazi F, Racanicchi S, Zardo G, Starnes LM, Mancini M, Travaglini L, et al. Epigenetic silencing of the myelopoiesis regulator microRNA-223 by the AML1/ETO oncoprotein. Cancer Cell. 2007;12:457–66.

    Article  CAS  Google Scholar 

  27. Wang L, Gural A, Sun XJ, Zhao X, Perna F, Huang G, et al. The leukemogenicity of AML1-ETO is dependent on site-specific lysine acetylation. Science. 2011;333:765–9.

    Article  CAS  Google Scholar 

  28. Shia WJ, Okumura AJ, Yan M, Sarkeshik A, Lo MC, Matsuura S, et al. PRMT1 interacts with AML1-ETO to promote its transcriptional activation and progenitor cell proliferative potential. Blood. 2012;119:4953–62.

    Article  CAS  Google Scholar 

  29. Hou J, Zhang H, Liu J, Zhao Z, Wang J, Lu Z, et al. Hypoxia regulates m6A-reader YTHDF2 to fuel cancer-promoting inflammation in hepatocellular carcinoma. Cancer Res. 2019;79(13 Suppl):Abstract nr 4319.

  30. Kühnl A, Gökbuget N, Kaiser M, Schlee C, Stroux A, Burmeister T. et al. Overexpression of LEF1 predicts unfavorable outcome in adultpatients with B-precursor acute lymphoblastic leukemia. Blood. 2011;118:6362–7.

    Article  Google Scholar 

  31. Scrucca L, Santucci A, Aversa F. Competing risk analysis using R: an easy guide for clinicians. Bone Marrow Transplant. 2007;40:381–7.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was partially supported by grants from the National Natural Science Foundation of China (82070149, 81870109, and 81670135 to X-NG), the Natural Science Foundation of Beijing Municipality (7202191 to X-NG).

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  1. These authors contributed equally: Ze Chen, Yang-Liu Shao, Li-Li Wang, Ji Lin

Authors and Affiliations

  1. Department of Hematology, Chinese PLA General Hospital, Beijing, China

    Ze Chen, Yang-Liu Shao, Li-Li Wang, Yi Ding, Bin-bin Gao, Dai-Hong Liu & Xiao-Ning Gao

  2. Department of Basic Medicine, Graduate School, Chinese PLA General Hospital, Beijing, China

    Ji Lin

  3. Department of Cardiology, Chinese PLA General Hospital, Beijing, China

    Ji-Bin Zhang

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Chen, Z., Shao, YL., Wang, LL. et al. YTHDF2 is a potential target of AML1/ETO-HIF1α loop-mediated cell proliferation in t(8;21) AML. Oncogene 40, 3786–3798 (2021). https://doi.org/10.1038/s41388-021-01818-1

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