Non-m⁶A RNA modifications in haematological malignancies

Abstract

Dysregulated RNA modifications, stemming from the aberrant expression and/or malfunction of RNA modification regulators operating through various pathways, play pivotal roles in driving the progression of haematological malignancies. Among RNA modifications, N⁶-methyladenosine (m⁶A) RNA modification, the most abundant internal mRNA modification, stands out as the most extensively studied modification. This prominence underscores the crucial role of the layer of epitranscriptomic regulation in controlling haematopoietic cell fate and therefore the development of haematological malignancies. Additionally, other RNA modifications (non-m⁶A RNA modifications) have gained increasing attention for their essential roles in haematological malignancies. Although the roles of the m⁶A modification machinery in haematopoietic malignancies have been well reviewed thus far, such reviews are lacking for non-m⁶A RNA modifications. In this review, we mainly focus on the roles and implications of non-m⁶A RNA modifications, including N⁴-acetylcytidine, pseudouridylation, 5-methylcytosine, adenosine to inosine editing, 2′-O-methylation, N¹-methyladenosine and N⁷-methylguanosine in haematopoietic malignancies. We summarise the regulatory enzymes and cellular functions of non-m⁶A RNA modifications, followed by the discussions of the recent studies on the biological roles and underlying mechanisms of non-m⁶A RNA modifications in haematological malignancies. We also highlight the potential of therapeutically targeting dysregulated non-m⁶A modifiers in blood cancer.

Keywords

epitranscriptomics / haematological malignancies / non-m ⁶A RNA modification

References

[1] Huang H, Weng H, Chen J. m6A modification in coding and non-coding RNAs: roles and therapeutic implications in cancer. Cancer Cell. 2020;37(3):270-288.

[2] Yoon K-J, Vissers C, Ming G-L, Song H. Epigenetics and epitranscriptomics in temporal patterning of cortical neural progenitor competence. J Cell Biol. 2018;217(6):1901-1914.

[3] Deng X, Qing Y, Horne D, Huang H, Chen J. The roles and implications of RNA m(6)A modification in cancer. Nat Rev Clin Oncol. 2023;20(8):507-526.

[4] Huang H, Weng H, Deng X, Chen J. RNA modifications in cancer: functions, mechanisms, and therapeutic implications. Annu Rev Cancer Biol. 2020;4:221-240.

[5] Cayir A. RNA modifications as emerging therapeutic targets. Wiley Interdiscip Rev RNA. 2022;13(4):e1702.

[6] Han L, Chen J, Su R. Epitranscriptomics in myeloid malignancies. Blood Sci. 2022;4(03):133-135.

[7] Zhang Y, Yang Y. Effects of m6A RNA methylation regulators on endometrial cancer. J Clin Lab Anal. 2021;35(9):e23942.

[8] Farooqi AA, Fayyaz S, Poltronieri P, Calin G, Mallardo M. Epigenetic deregulation in cancer: enzyme players and non-coding RNAs. Semin Cancer Biol. 2022;83:197-207.

[9] Esteve-Puig R, Bueno-Costa A, Esteller M. Writers, readers and erasers of RNA modifications in cancer. Cancer Lett. 2020;474:127-137.

[10] Cusenza VY, Tameni A, Neri A, Frazzi R. The lncRNA epigenetics: the significance of m6A and m5C lncRNA modifications in cancer. Front Oncol. 2023;13:1063636.

[11] Li Z, Weng H, Su R, et al. FTO plays an oncogenic role in acute myeloid leukemia as a N6-methyladenosine RNA demethylase. Cancer Cell. 2017;31(1):127-141.

[12] Su R, Dong L, Li C, et al. R-2HG exhibits anti-tumor activity by targeting FTO/m(6)A/MYC/CEBPA signaling. Cell. 2018;172(1-2):90-105. e123.

[13] Weng H, Huang H, Wu H, et al. METTL14 inhibits hematopoietic stem/progenitor differentiation and promotes leukemogenesis via mRNA m(6)A modification. Cell Stem Cell. 2018;22(2):191-205. e199.

[14] Vu LP, Pickering BF, Cheng Y, et al. The N(6)-methyladenosine (m(6)A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells. Nat Med. 2017;23(11):1369-1376.

[15] Shen C, Sheng Y, Zhu AC, et al. RNA demethylase ALKBH5 selectively promotes tumorigenesis and cancer stem cell self-renewal in acute myeloid leukemia. Cell Stem Cell. 2020;27(1):64-80. e69.

[16] Paris J, Morgan M, Campos J, et al. Targeting the RNA m(6)A reader YTHDF2 selectively compromises cancer stem cells in acute myeloid leukemia. Cell Stem Cell. 2019;25(1):137-148. e136.

[17] Huang Y, Su R, Sheng Y, et al. Small-molecule targeting of oncogenic FTO demethylase in acute myeloid leukemia. Cancer Cell. 2019;35:677-691.

[18] Barbieri I, Tzelepis K, Pandolfini L, et al. Promoter-bound METTL3 maintains myeloid leukaemia by m(6)A-dependent translation control. Nature. 2017;552(7683):126-131.

[19] Wang J, Li Y, Wang P, et al. Leukemogenic chromatin alterations promote AML leukemia stem cells via a KDM4C‒ALKBH5‒AXL signaling axis. Cell Stem Cell. 2020;27(1):81-97. e88.

[20] Su R, Dong L, Li Y, et al. Targeting FTO suppresses cancer stem cell maintenance and immune evasion. Cancer Cell. 2020;38(1):79-96. e11.

[21] Qing Y, Dong L, Gao L, et al. R-2-hydroxyglutarate attenuates aerobic glycolysis in leukemia by targeting the FTO/m(6)A/PFKP/LDHB axis. Mol Cell. 2021;81(5):922-939. e929.

[22] Cheng Y, Xie W, Pickering BF, et al. N(6)-Methyladenosine on mRNA facilitates a phase-separated nuclear body that suppresses myeloid leukemic differentiation. Cancer Cell. 2021;39(7):958-972. e958.

[23] Sheng Y, Wei J, Yu F, et al. A critical role of nuclear m6A reader YTHDC1 in leukemogenesis by regulating MCM complex-mediated DNA replication. Blood. 2021;138(26):2838-2852.

[24] Weng H, Huang F, Yu Z, et al. The m(6)A reader IGF2BP2 regulates glutamine metabolism and represents a therapeutic target in acute myeloid leukemia. Cancer Cell. 2022;40:1-17.

[25] Zhang Z, Zhou K, Han L, et al. RNA m(6)A reader YTHDF2 facilitates precursor miR-126 maturation to promote acute myeloid leukemia progression. Genes Dis. 2024;11(1):382-396.

[26] Li Y, Xue M, Deng X, et al. TET2-mediated mRNA demethylation regulates leukemia stem cell homing and self-renewal. Cell Stem Cell. 2023;30(8):1072-1090. e1010.

[27] Han L, Dong L, Leung K, et al. METTL16 drives leukemogenesis and leukemia stem cell self-renewal by reprogramming BCAA metabolism. Cell Stem Cell. 2023;30(1):52-68. e13.

[28] Weng H, Huang H, Chen J. RNA N (6)-methyladenosine modification in normal and malignant hematopoiesis. Adv Exp Med Biol. 2019;1143:75-93.

[29] Deng X, Su R, Weng H, Huang H, Li Z, Chen J. RNA N(6)-methyladenosine modification in cancers: current status and perspectives. Cell Res. 2018;28(5):507-517.

[30] Qing Y, Su R, Chen J. RNA modifications in hematopoietic malignancies: a new research frontier. Blood. 2021;138(8):637-648.

[31] Sun H, Li K, Liu C, Yi C. Regulation and functions of non-m(6)A mRNA modifications. Nat Rev Mol Cell Biol. 2023;24(10):714-731.

[32] Jin G, Xu M, Zou M, Duan S. The processing, gene regulation, biological functions, and clinical relevance of N4-acetylcytidine on RNA: a systematic review. Mol Ther Nucleic Acids. 2020;20:13-24.

[33] Zachau HG, Dütting B, Feldmann H. The structures of two serine transfer ribonucleic acids. Hoppe Seylers Z Physiol Chem. 1966;347(4):212-235.

[34] Bruenger E, Kowalak JA, Kuchino Y, et al. 5S rRNA modification in the hyperthermophilic archaea Sulfolobus solfataricus and Pyrodictium occultum. FASEB J. 1993;7(1):196-200.

[35] Arango D, Sturgill D, Alhusaini N, et al. Acetylation of cytidine in mRNA promotes translation efficiency. Cell. 2018;175(7):1872-1886. e1824.

[36] Liu R, Wubulikasimu Z, Cai R, et al. NAT10-mediated N4-acetylcytidine mRNA modification regulates self-renewal in human embryonic stem cells. Nucleic Acids Res. 2023;51(16):8514-8531.

[37] Arango D, Sturgill D, Yang R, et al. Direct epitranscriptomic regulation of mammalian translation initiation through N4-acetylcytidine. Mol Cell. 2022;82(15):2797-2814. e2711.

[38] Sas-Chen A, Thomas JM, Matzov D, et al. Dynamic RNA acetylation revealed by quantitative cross-evolutionary mapping. Nature. 2020;583(7817):638-643.

[39] Ikeuchi Y, Kitahara K, Suzuki T. The RNA acetyltransferase driven by ATP hydrolysis synthesizes N4-acetylcytidine of tRNA anticodon. EMBO J. 2008;27(16):2194-2203.

[40] Sharma S, Langhendries J-L, Watzinger P, Kötter P, Entian K-D, Lafontaine DL. Yeast Kre33 and human NAT10 are conserved 18S rRNA cytosine acetyltransferases that modify tRNAs assisted by the adaptor Tan1/THUMPD1. Nucleic Acids Res. 2015;43(4):2242-2258.

[41] Liao L, He Y, Li SJ, et al. Lysine 2-hydroxyisobutyrylation of NAT10 promotes cancer metastasis in an ac4C-dependent manner. Cell Res. 2023;33(5):355-371.

[42] Cerneckis J, Cui Q, He C, Yi C, Shi Y. Decoding pseudouridine: an emerging target for therapeutic development. Trends Pharmacol Sci. 2022;43(6):522-535.

[43] Dai Q, Zhang LS, Sun HL, et al. Quantitative sequencing using BID-seq uncovers abundant pseudouridines in mammalian mRNA at base resolution. Nat Biotechnol. 2023;41(3):344-354.

[44] Zhang M, Jiang Z, Ma Y, et al. Quantitative profiling of pseudouridylation landscape in the human transcriptome. Nat Chem Biol. 2023;19(10):1185-1195.

[45] Molinie B, Wang J, Lim KS, et al. m(6)A-LAIC-seq reveals the census and complexity of the m(6)A epitranscriptome. Nat Methods. 2016;13(8):692-698.

[46] Roundtree IA, Evans ME, Pan T, He C. Dynamic RNA modifications in gene expression regulation. Cell. 2017;169(7):1187-1200.

[47] Stockert JA, Weil R, Yadav KK, Kyprianou N, Tewari AK. Pseudouridine as a novel biomarker in prostate cancer. Paper presented at: Urologic Oncology: Seminars and Original Investigations. 2021;39(1):63-71.

[48] Wu G, Yu AT, Kantartzis A, Yu YT. Functions and mechanisms of spliceosomal small nuclear RNA pseudouridylation. Wiley Interdiscip Rev RNA. 2011;2(4):571-581.

[49] Wu H, Feigon J. H/ACA small nucleolar RNA pseudouridylation pockets bind substrate RNA to form three-way junctions that position the target U for modification. Proc Natl Acad Sci U S A. 2007;104(16):6655-6660.

[50] De Zoysa MD, Yu Y-T. Posttranscriptional RNA pseudouridylation. Enzymes. 2017;41:151-167.

[51] Li S, Duan J, Li D, Ma S, Ye K. Structure of the Shq1‒Cbf5‒Nop10‒Gar1 complex and implications for H/ACA RNP biogenesis and dyskeratosis congenita. EMBO J. 2011;30(24):5010-5020.

[52] Borchardt EK, Martinez NM, Gilbert WV. Regulation and function of RNA pseudouridylation in human cells. Annu Rev Genet. 2020;54:309-336.

[53] Schwartz S, Bernstein DA, Mumbach MR, et al. Transcriptome-wide mapping reveals widespread dynamic-regulated pseudouridylation of ncRNA and mRNA. Cell. 2014;159(1):148-162.

[54] Hudson GA, Bloomingdale RJ, Znosko BM. Thermodynamic contribution and nearest-neighbor parameters of pseudouridine-adenosine base pairs in oligoribonucleotides. RNA. 2013;19(11):1474-1482.

[55] Kierzek E, Malgowska M, Lisowiec J, Turner DH, Gdaniec Z, Kierzek R. The contribution of pseudouridine to stabilities and structure of RNAs. Nucleic Acids Res. 2014;42(5):3492-3501.

[56] Anderson BR, Muramatsu H, Nallagatla SR, et al. Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation. Nucleic Acids Res. 2010;38(17):5884-5892.

[57] Nallagatla SR, Bevilacqua PC. Nucleoside modifications modulate activation of the protein kinase PKR in an RNA structure-specific manner. RNA. 2008;14(6):1201-1213.

[58] Karijolich J, Yu YT. Converting nonsense codons into sense codons by targeted pseudouridylation. Nature. 2011;474(7351):395-398.

[59] Fernandez IS, Ng CL, Kelley AC, Wu G, Yu YT, Ramakrishnan V. Unusual base pairing during the decoding of a stop codon by the ribosome. Nature. 2013;500(7460):107-110.

[60] Trixl L, Lusser A. The dynamic RNA modification 5-methylcytosine and its emerging role as an epitranscriptomic mark. Wiley Interdiscip Rev RNA. 2019;10(1):e1510.

[61] Desrosiers R, Friderici K, Rottman F. Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. Proc Natl Acad Sci U S A. 1974;71(10):3971-3975.

[62] Gao Y, Fang J. RNA 5-methylcytosine modification and its emerging role as an epitranscriptomic mark. RNA Biol. 2021;18(suppl 1):117-127.

[63] Huber SM, van Delft P, Mendil L, et al. Formation and abundance of 5-hydroxymethylcytosine in RNA. Chembiochem. 2015;16(5):752-755.

[64] Li M, Tao Z, Zhao Y, et al. 5-Methylcytosine RNA methyltransferases and their potential roles in cancer. J Transl Med. 2022;20(1):214.

[65] Liao H, Gaur A, McConie H, et al. Human NOP2/NSUN1 regulates ribosome biogenesis through non-catalytic complex formation with box C/D snoRNPs. Nucleic Acids Res. 2022;50(18):10695-10716.

[66] Wei H, Jiang S, Chen L, He C, Wu S, Peng H. Characterization of cytosine methylation and the DNA methyltransferases of Toxoplasma gondii. Int J Biol Sci. 2017;13(4):458-470.

[67] Zhang Q, Liu F, Chen W, et al. The role of RNA m5C modification in cancer metastasis. Int J Biol Sci. 2021;17(13):3369.

[68] Chen YS, Yang WL, Zhao YL, Yang YG. Dynamic transcriptomic m(5) C and its regulatory role in RNA processing. Wiley Interdiscip Rev RNA. 2021;12(4):e1639.

[69] Yang Y, Wang L, Han X, et al. RNA 5-methylcytosine facilitates the maternal-to-zygotic transition by preventing maternal mRNA decay. Mol Cell. 2019;75(6):1188-1202. e1111.

[70] Tuorto F, Herbst F, Alerasool N, et al. The tRNA methyltransferase Dnmt2 is required for accurate polypeptide synthesis during haematopoiesis. EMBO J. 2015;34(18):2350-2362.

[71] Slotkin W, Nishikura K. Adenosine-to-inosine RNA editing and human disease. Genome Med. 2013;5(11):1-13.

[72] Wang C, Zou J, Ma X, Wang E, Peng G. Mechanisms and implications of ADAR-mediated RNA editing in cancer. Cancer Lett. 2017;411:27-34.

[73] Fritzell K, Xu L-D, Lagergren J, Öhman M. ADARs and editing: the role of A-to-I RNA modification in cancer progression. Paper presented at: Seminars in Cell & Developmental Biology. 2018;79:123-130.

[74] Rajendren S, Ye X, Dunker W, Richardson A, Karijolich J. The cellular and KSHV A-to-I RNA editome in primary effusion lymphoma and its role in the viral lifecycle. Nat Commun. 2023;14(1):1367.

[75] Rueter SM, Dawson TR, Emeson RB. Regulation of alternative splicing by RNA editing. Nature. 1999;399(6731):75-80.

[76] Nishikura K. A-to-I editing of coding and non-coding RNAs by ADARs. Nat Rev Mol Cell Biol. 2016;17(2):83-96.

[77] Eisenberg E, Levanon EY. A-to-I RNA editing—immune protector and transcriptome diversifier. Nat Rev Genet. 2018;19(8):473-490.

[78] Ivanov A, Memczak S, Wyler E, et al. Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals. Cell Rep. 2015;10(2):170-177.

[79] Stellos K, Gatsiou A, Stamatelopoulos K, et al. Adenosine-to-inosine RNA editing controls cathepsin S expression in atherosclerosis by enabling HuR-mediated post-transcriptional regulation. Nat Med. 2016;22(10):1140-1150.

[80] Chan TH, Lin CH, Qi L, et al. A disrupted RNA editing balance mediated by ADARs (adenosine DeAminases that act on RNA) in human hepatocellular carcinoma. Gut. 2014;63(5):832-843.

[81] Shoshan E, Mobley AK, Braeuer RR, et al. Reduced adenosine-to-inosine miR-455-5p editing promotes melanoma growth and metastasis. Nat Cell Biol. 2015;17(3):311-321.

[82] Nakano M, Nakajima M. Significance of A-to-I RNA editing of transcripts modulating pharmacokinetics and pharmacodynamics. Pharmacol Ther. 2018;181:13-21.

[83] Jain M, Mann TD, Stulic M, et al. RNA editing of Filamin A pre-mRNA regulates vascular contraction and diastolic blood pressure. EMBO J. 2018;37(19):e94813.

[84] Nakano M, Fukami T, Gotoh S, Nakajima M. A-to-I RNA editing up-regulates human dihydrofolate reductase in breast cancer. J Biol Chem. 2017;292(12):4873-4884.

[85] Park E, Jiang Y, Hao L, Hui J, Xing Y. Genetic variation and microRNA targeting of A-to-I RNA editing fine tune human tissue transcriptomes. Genome Biol. 2021;22(1):77.

[86] Dimitrova DG, Teysset L, Carré C. RNA 2′-O-methylation (Nm) modification in human diseases. Genes. 2019;10(2):117.

[87] Angelova MT, Dimitrova DG, Da Silva B, et al. tRNA 2′-O-methylation by a duo of TRM7/FTSJ1 proteins modulates small RNA silencing in Drosophila. Nucleic Acids Res. 2020;48(4):2050-2072.

[88] Drazkowska K, Tomecki R, Warminski M, et al. 2'-O-Methylation of the second transcribed nucleotide within the mRNA 5' cap impacts the protein production level in a cell-specific manner and contributes to RNA immune evasion. Nucleic Acids Res. 2022;50(16):9051-9071.

[89] Dai Q, Moshitch-Moshkovitz S, Han D, et al. Nm-seq maps 2'-O-methylation sites in human mRNA with base precision. Nat Methods. 2017;14(7):695-698.

[90] Ayadi L, Galvanin A, Pichot F, Marchand V, Motorin Y. RNA ribose methylation (2′-O-methylation): occurrence, biosynthesis and biological functions. Biochim Biophys Acta Gene Regul Mech. 2019;1862(3):253-269.

[91] Pauli C, Liu Y, Rohde C, et al. Site-specific methylation of 18S ribosomal RNA by SNORD42A is required for acute myeloid leukemia cell proliferation. Blood. 2020;135(23):2059-2070.

[92] Li J, Wang YN, Xu BS, et al. Intellectual disability-associated gene ftsj1 is responsible for 2′-O-methylation of specific tRNAs. EMBO Rep. 2020;21(8):e50095.

[93] Ringeard M, Marchand V, Decroly E, Motorin Y, Bennasser Y. FTSJ3 is an RNA 2′-O-methyltransferase recruited by HIV to avoid innate immune sensing. Nature. 2019;565(7740):500-504.

[94] He Q, Yang L, Gao K, et al. FTSJ1 regulates tRNA 2′-O-methyladenosine modification and suppresses the malignancy of NSCLC via inhibiting DRAM1 expression. Cell Death Dis. 2020;11(5):348.

[95] Li H, Dong H, Xu B, et al. A dual role of human tRNA methyltransferase hTrmt13 in regulating translation and transcription. EMBO J. 2022;41(6):e108544.

[96] Inesta-Vaquera F, Cowling VH. Regulation and function of CMTR1-dependent mRNA cap methylation. Wiley Interdiscip Rev RNA. 2017;8(6):e1450.

[97] Peng L, Zhang F, Shang R, et al. Identification of substrates of the small RNA methyltransferase Hen1 in mouse spermatogonial stem cells and analysis of its methyl-transfer domain. J Biol Chem. 2018;293(26):9981-9994.

[98] Liang H, Jiao Z, Rong W, et al. 3′-Terminal 2′-O-methylation of lung cancer miR-21-5p enhances its stability and association with Argonaute 2. Nucleic Acids Res. 2020;48(13):7027-7040.

[99] Lim SL, Qu ZP, Kortschak RD, et al. HENMT1 and piRNA stability are required for adult male germ cell transposon repression and to define the spermatogenic program in the mouse. PLoS Genet. 2015;11(10):e1005620.

[100] Elliott BA, Ho HT, Ranganathan SV, et al. Modification of messenger RNA by 2′-O-methylation regulates gene expression in vivo. Nat Commun. 2019;10(1):3401.

[101] Choi J, Indrisiunaite G, DeMirci H, et al. 2′-O-methylation in mRNA disrupts tRNA decoding during translation elongation. Nat Struct Mol Biol. 2018;25(3):208-216.

[102] Liu J, Chen C, Wang Y, et al. Comprehensive of N1-methyladenosine modifications patterns and immunological characteristics in ovarian cancer. Front Immunol. 2021:12:746647.

[103] Zhang C, Jia G. Reversible RNA modification N(1)-methyladenosine (m(1)A) in mRNA and tRNA. Genomics Proteomics Bioinform. 2018;16(3):155-161.

[104] Dominissini D, Nachtergaele S, Moshitch-Moshkovitz S, et al. The dynamic N(1)-methyladenosine methylome in eukaryotic messenger RNA. Nature. 2016;530(7591):441-446.

[105] Li X, Xiong X, Wang K, et al. Transcriptome-wide mapping reveals reversible and dynamic N(1)-methyladenosine methylome. Nat Chem Biol. 2016;12(5):311-316.

[106] Xiong W, Zhao Y, Wei Z, et al. N1-methyladenosine formation, gene regulation, biological functions, and clinical relevance. Mol Ther. 2023;31(2):308-330.

[107] Safra M, Sas-Chen A, Nir R, et al. The m1A landscape on cytosolic and mitochondrial mRNA at single-base resolution. Nature. 2017;551(7679):251-255.

[108] Bar-Yaacov D, Frumkin I, Yashiro Y, et al. Mitochondrial 16S rRNA is methylated by tRNA methyltransferase TRMT61B in all vertebrates. PLoS Biol. 2016;14(9):e1002557.

[109] Liu F, Clark W, Luo G, et al. ALKBH1-mediated tRNA demethylation regulates translation. Cell. 2016;167(3):816-828. e816.

[110] Wei J, Liu F, Lu Z, et al. Differential m(6)A, m(6)A(m), and m(1)A demethylation mediated by FTO in the cell nucleus and cytoplasm. Mol Cell. 2018;71(6):973-985. e975.

[111] Dai X, Wang T, Gonzalez G, Wang Y. Identification of YTH domain-containing proteins as the readers for N1-methyladenosine in RNA. Anal Chem. 2018;90(11):6380-6384.

[112] Seo KW, Kleiner RE. YTHDF2 recognition of N(1)-methyladenosine (m(1)A)-modified RNA is associated with transcript destabilization. ACS Chem Biol. 2020;15(1):132-139.

[113] Woo HH, Chambers SK. Human ALKBH3-induced m(1)A demethylation increases the CSF-1 mRNA stability in breast and ovarian cancer cells. Biochim Biophys Acta Gene Regul Mech. 2019;1862(1):35-46.

[114] Wu Y, Chen Z, Xie G, et al. RNA m(1)A methylation regulates glycolysis of cancer cells through modulating ATP5D. Proc Natl Acad Sci U S A. 2022;119(28):e2119038119.

[115] Li X, Xiong X, Zhang M, et al. Base-resolution mapping reveals distinct m(1)A methylome in nuclear- and mitochondrial-encoded transcripts. Mol Cell. 2017;68(5):993-1005. e1009.

[116] Cowling VH. Regulation of mRNA cap methylation. Biochem J. 2010;425(2):295-302.

[117] Jackson RJ, Hellen CU, Pestova TV. The mechanism of eukaryotic translation initiation and principles of its regulation. Nat Rev Mol Cell Biol. 2010;11(2):113-127.

[118] Zhang LS, Liu C, Ma H, et al. Transcriptome-wide mapping of internal N(7)-methylguanosine methylome in mammalian mRNA. Mol Cell. 2019;74(6):1304-1316. e1308.

[119] Zhang LS, Ju CW, Liu C, et al. m(7)G-quant-seq: quantitative detection of RNA internal N(7)-methylguanosine. ACS Chem Biol. 2022;17(12):3306-3312.

[120] Chu JM, Ye TT, Ma CJ, et al. Existence of internal N7-methylguanosine modification in mRNA determined by differential enzyme treatment coupled with mass spectrometry analysis. ACS Chem Biol. 2018;13(12):3243-3250.

[121] Zhang L-S, Liu C, Ma H, et al. Transcriptome-wide mapping of internal N7-methylguanosine methylome in mammalian mRNA. Mol Cell. 2019;74(6):1304-1316. e1308.

[122] Malbec L, Zhang T, Chen Y-S, et al. Dynamic methylome of internal mRNA N 7-methylguanosine and its regulatory role in translation. Cell Res. 2019;29(11):927-941.

[123] Zhao Z, Qing Y, Dong L, et al. QKI shuttles internal m(7)G-modified transcripts into stress granules and modulates mRNA metabolism. Cell. 2023;186(15):3208-3226. e3227.

[124] Xia P, Zhang H, Xu K, et al. MYC-targeted WDR4 promotes proliferation, metastasis, and sorafenib resistance by inducing CCNB1 translation in hepatocellular carcinoma. Cell Death Dis. 2021;12(7):691.

[125] Jin C, Wang T, Zhang D, et al. Acetyltransferase NAT10 regulates the Wnt/β-catenin signaling pathway to promote colorectal cancer progression via ac4C acetylation of KIF23 mRNA. J Exp Clin Cancer Res. 2022;41(1):345.

[126] Li Q, Liu X, Jin K, et al. NAT10 is upregulated in hepatocellular carcinoma and enhances mutant p53 activity. BMC Cancer. 2017;17(1):1-10.

[127] Liu Z, Liu X, Li Y, et al. miR-6716-5p promotes metastasis of colorectal cancer through downregulating NAT10 expression. Cancer Manag Res. 2019;11:5317.

[128] Oh T-I, Lee Y-M, Lim B-O, Lim J-H. Inhibition of NAT10 suppresses melanogenesis and melanoma growth by attenuating microphthalmia-associated transcription factor (MITF) expression. Int J Mol Sci. 2017;18(9):1924.

[129] Wei W, Zhang S, Han H, et al. NAT10-mediated ac4C tRNA modification promotes EGFR mRNA translation and gefitinib resistance in cancer. Cell Rep. 2023;42(7):112810.

[130] Liang P, Hu R, Liu Z, Miao M, Jiang H, Li C. NAT10 upregulation indicates a poor prognosis in acute myeloid leukemia. Curr Probl Cancer. 2020;44(2):100491.

[131] Zi J, Han Q, Gu S, et al. Targeting NAT10 induces apoptosis associated with enhancing endoplasmic reticulum stress in acute myeloid leukemia cells. Front Oncol. 2020;10:598107.

[132] Wei R, Cui X, Min J, et al. NAT10 promotes cell proliferation by acetylating CEP170 mRNA to enhance translation efficiency in multiple myeloma. Acta Pharm Sin B. 2022;12(8):3313-3325.

[133] Zhang Y, Deng Z, Sun S, et al. NAT10 acetylates BCL-XL mRNA to promote the proliferation of multiple myeloma cells through PI3K-AKT pathway. Front Oncol. 2022;12:967811.

[134] Li K, Liu J, Yang X, Tu Z, Huang K, Zhu X. Pan-cancer analysis of N4-acetylcytidine adaptor THUMPD1 as a predictor for prognosis and immunotherapy. Biosci Rep. 2021;41(12):BSR20212300.

[135] Poncet D, Belleville A, t'Kint de Roodenbeke C, et al. Changes in the expression of telomere maintenance genes suggest global telomere dysfunction in B-chronic lymphocytic leukemia. Blood. 2008;111(4):2388-2391.

[136] Rocchi L, Barbosa AJ, Onofrillo C, Del Rio A, Montanaro L. Inhibition of human dyskerin as a new approach to target ribosome biogenesis. PLoS One. 2014;9(7):e101971.

[137] Montanaro L. Dyskerin and cancer: more than telomerase. The defect in mRNA translation helps in explaining how a proliferative defect leads to cancer. J Pathol. 2010;222(4):345-349.

[138] Su H, Hu J, Huang L, et al. SHQ1 regulation of RNA splicing is required for T-lymphoblastic leukemia cell survival. Nat Commun. 2018;9(1):4281.

[139] Guzzi N, Cieśla M, Ngoc PCT, et al. Pseudouridylation of tRNA-derived fragments steers translational control in stem cells. Cell. 2018;173(5):1204-1216. e1226.

[140] Guzzi N, Muthukumar S, Cieśla M, et al. Pseudouridine-modified tRNA fragments repress aberrant protein synthesis and predict leukaemic progression in myelodysplastic syndrome. Nat Cell Biol. 2022;24(3):299-306.

[141] He Y, Yu X, Zhang M, Guo W. Pan-cancer analysis of m5C regulator genes reveals consistent epigenetic landscape changes in multiple cancers. World J Surg Oncol. 2021;19(1):1-12.

[142] Nombela P, Miguel-López B, Blanco S. The role of m6A, m5C and Ψ RNA modifications in cancer: novel therapeutic opportunities. Mol Cancer. 2021;20(1):1-30.

[143] Chellamuthu A, Gray SG. The RNA methyltransferase NSUN2 and its potential roles in cancer. Cells. 2020;9(8):1758.

[144] Ma B, Wang P. NSUN6, a gene related with m5c methylation, may serve as a biomarker for pan-cancer. Research Square. 2022.

[145] Cheng JX, Chen L, Li Y, et al. RNA cytosine methylation and methyltransferases mediate chromatin organization and 5-azacytidine response and resistance in leukaemia. Nat Commun. 2018;9(1):1163.

[146] Schaefer M, Hagemann S, Hanna K, Lyko F. Azacytidine inhibits RNA methylation at DNMT2 target sites in human cancer cell lines. Cancer Res. 2009;69(20):8127-8132.

[147] Anadón C, Guil S, Simó-Riudalbas L, et al. Gene amplification-associated overexpression of the RNA editing enzyme ADAR1 enhances human lung tumorigenesis. Oncogene. 2016;35(33):4407-4413.

[148] Shi L, Yan P, Liang Y, et al. Circular RNA expression is suppressed by androgen receptor (AR)-regulated adenosine deaminase that acts on RNA (ADAR1) in human hepatocellular carcinoma. Cell Death Dis. 2017;8(11):e3171.

[149] Qiao J-J, Chan THM, Qin Y-R, Chen L. ADAR1: a promising new biomarker for esophageal squamous cell carcinoma? Expert Rev Anticancer Ther. 2014;14(8):865-868.

[150] Jiang Q, Crews LA, Barrett CL, et al. ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia. Proc Natl Acad Sci U S A. 2013;110(3):1041-1046.

[151] Zipeto MA, Court AC, Sadarangani A, et al. ADAR1 activation drives leukemia stem cell self-renewal by impairing Let-7 biogenesis. Cell Stem Cell. 2016;19(2):177-191.

[152] Tomaselli S, Galeano F, Alon S, et al. Modulation of microRNA editing, expression and processing by ADAR2 deaminase in glioblastoma. Genome Biol. 2015;16(1):1-19.

[153] Guo M, Chan TMH, Zhou Q, et al. Core-binding factor fusion downregulation of ADAR2 RNA editing contributes to AML leukemogenesis. Blood. 2023;141(25):3078-3090.

[154] You X-J, Li L, Ji T-T, Xie N-B, Yuan B-F, Feng Y-Q. 6-Thioguanine incorporates into RNA and induces adenosine-to-inosine editing in acute lymphoblastic leukemia cells. Chin Chem Lett. 2023;34(1):107181.

[155] Lazzari E, Mondala PK, Santos ND, et al. Alu-dependent RNA editing of GLI1 promotes malignant regeneration in multiple myeloma. Nat Commun. 2017;8(1):1922.

[156] Hanamura I. Gain/amplification of chromosome arm 1q21 in multiple myeloma. Cancers. 2021;13(2):256.

[157] Crews L, Lazzari E, Mondala P, et al. ADAR1-mediated GLI1 editing promotes malignant self-renewal in multiple myeloma. Blood. 2017;130:1204.

[158] Zhang J, He P, Wang X, Wei S, Ma L, Zhao J. A novel model of tumor-infiltrating B lymphocyte specific RNA-binding protein-related genes with potential prognostic value and therapeutic targets in multiple myeloma. Front Genet. 2021;12:778715.

[159] Shi J, Zhu T, Lin H, et al. Proteotranscriptomics of ocular adnexal B-cell lymphoma reveals an oncogenic role of alternative splicing and identifies a diagnostic marker. J Exp Clin Cancer Res. 2022;41(1):234.

[160] Ohki K, Kiyokawa N, Watanabe S, et al. Characteristics of genetic alterations of peripheral T-cell lymphoma in childhood including identification of novel fusion genes: the Japan Children's Cancer Group (JCCG). Br J Haematol. 2021;194(4):718-729.

[161] Pecori R, Ren W, Pirmoradian M, et al. ADAR1-mediated RNA editing promotes B cell lymphomagenesis. iScience. 2023;26(6):106864.

[162] Zipeto M, Jiang Q, Robertson LC, Jamieson CH. ADAR1-mediated microRNA regulation and blast crisis leukemia stem cell generation in chronic myeloid leukemia. Cancer Res. 2014;74(19_suppl):1912-1912.

[163] Huang W, Sun Y-M, Pan Q, et al. The snoRNA-like lncRNA LNC-SNO49AB drives leukemia by activating the RNA-editing enzyme ADAR1. Cell Discov. 2022;8(1):117.

[164] Gassner FJ, Zaborsky N, Buchumenski I, et al. RNA editing contributes to epitranscriptome diversity in chronic lymphocytic leukemia. Leukemia. 2021;35(4):1053-1063.

[165] Zhou F, Aroua N, Liu Y, et al. A dynamic rRNA ribomethylome drives stemness in acute myeloid leukemia. Cancer Discov. 2023;13(2):332-347.

[166] Jiang W, Wang H, Zhou S, et al. Establishment of a typing model for diffuse large B-cell lymphoma based on B-cell receptor repertoire sequencing. BMC Cancer. 2021;21(1):1-10.

[167] Begik O, Lucas MC, Liu H, Ramirez JM, Mattick JS, Novoa EM. Integrative analyses of the RNA modification machinery reveal tissue-and cancer-specific signatures. Genome Biol. 2020;21:1-24.

[168] Zhou F, Liu Y, Rohde C, et al. AML1-ETO requires enhanced C/D box snoRNA/RNP formation to induce self-renewal and leukaemia. Nat Cell Biol. 2017;19(7):844-855.

[169] Esteve-Puig R, Climent F, Piñeyro D, et al. Epigenetic loss of m1A RNA demethylase ALKBH3 in Hodgkin lymphoma targets collagen, conferring poor clinical outcome. Blood. 2021;137(7):994-999.

[170] Assouline S, Culjkovic B, Cocolakis E, et al. Molecular targeting of the oncogene eIF4E in acute myeloid leukemia (AML): a proof-of-principle clinical trial with ribavirin. Blood. 2009;114(2):257-260.

[171] Orellana EA, Liu Q, Yankova E, et al. METTL1-mediated m7G modification of Arg-TCT tRNA drives oncogenic transformation. Mol Cell. 2021;81(16):3323-3338. e3314.

[172] Crews LA, Ma W, Ladel L, et al. Reversal of malignant ADAR1 splice isoform switching with Rebecsinib. Cell Stem Cell. 2023;30(3):250-263. e256.

[173] Dalhat MH, Altayb HN, Khan MI, Choudhry H. Structural insights of human N-acetyltransferase 10 and identification of its potential novel inhibitors. Sci Rep. 2021;11(1):6051.

[174] Shrimp JH, Jing Y, Gamage ST, et al. Remodelin is a cryptic assay interference chemotype that does not inhibit NAT10-dependent cytidine acetylation. ACS Med Chem Lett. 2020;12(6):887-892.

[175] Vogler W, Trulock P. Phase I study of pyrazofurin in refractory acute myelogenous leukemia. Cancer Treat Rep. 1978;62(10):1569-1571.

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