{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:31:24Z","timestamp":1790692284791,"version":"4.1.0"},"reference-count":78,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T00:00:00Z","timestamp":1762473600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T00:00:00Z","timestamp":1762473600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000054","name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA266256"],"award-info":[{"award-number":["R01CA266256"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011541","name":"U.S. Department of Health & Human Services | NIH | NCI | Division of Cancer Epidemiology and Genetics, National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA248019"],"award-info":[{"award-number":["R01CA248019"]}],"id":[{"id":"10.13039\/100011541","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Long non-coding RNAs (lncRNAs) and RNA N\u2076-methyladenosine (m\n                    <jats:sup>6<\/jats:sup>\n                    A) have been linked to leukemia drug resistance. However, whether and how lncRNAs and m\n                    <jats:sup>6<\/jats:sup>\n                    A coordinately regulate resistance remain elusive. Here, we show that many differentially expressed lncRNAs enrich m\n                    <jats:sup>6<\/jats:sup>\n                    A, and more lncRNAs tend to have higher m\n                    <jats:sup>6<\/jats:sup>\n                    A content in CML cells resistant to tyrosine kinase inhibitors (TKIs). We demonstrate the broad clinical relevance of our findings, showing that upregulation of top-ranked lncRNAs (e.g., SENCR, PROX1-AS1, LINC00892) in TKI-resistant cell lines occurs in CML patients at the diagnostic stage, blast crisis phase, or not responding to TKIs compared to the chronic phase or TKI responders, respectively. Higher lncRNAs predict drug resistance and shorter survival duration. The knockdown of SENCR, PROX1-AS1, or LINC00892 restores TKI sensitivity. Mechanistically, upregulation of PROX1-AS1, SENCR, and LINC00892 results from FTO-dependent m\n                    <jats:sup>6<\/jats:sup>\n                    A hypomethylation that stabilizes lncRNA transcripts and empowers resistant cell growth through overexpression of PI3K signaling mediators (e.g., ITGA2, F2R, COL6A1). Treatment with PI3K inhibitor alpelisib eradicates resistant cells in vitro and in vivo, with prolonged survival of leukemic mice through downregulation of F2R, ITGA2, and COL6A1. Thus, the lncRNA-m\n                    <jats:sup>6<\/jats:sup>\n                    A-PI3K cascade represents a new non-genetic predictor for drug resistance and poorer prognosis in cancer, and a pan-cancer mechanism underlying TKI resistance.\n                  <\/jats:p>","DOI":"10.1038\/s41419-025-08045-6","type":"journal-article","created":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T13:04:03Z","timestamp":1762520643000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The RNA N6-methyladenosine methylome coordinates long non-coding RNAs to mediate cancer drug resistance by activating PI3K signaling"],"prefix":"10.1038","volume":"16","author":[{"given":"Yanhong","family":"Tan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changli","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sicheng","family":"Bian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiqin","family":"Bian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanan","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wencke","family":"Walter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiuxia","family":"Pang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuchao","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4210-0258","authenticated-orcid":false,"given":"Wenzheng","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingli","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aref","family":"Al-Kali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark R.","family":"Litzow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaonan","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhua","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9512-2240","authenticated-orcid":false,"given":"Rendong","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregor","family":"Hoermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Tse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shujun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,7]]},"reference":[{"key":"8045_CR1","doi-asserted-by":"publisher","first-page":"3040","DOI":"10.1038\/s41375-021-01436-6","volume":"35","author":"EA Bruford","year":"2021","unstructured":"Bruford EA, Antonescu CR, Carroll AJ, Chinnaiyan A, Cree IA, Cross NCP, et al. HUGO Gene Nomenclature Committee (HGNC) recommendations for the designation of gene fusions. Leukemia. 2021;35:3040\u20133.","journal-title":"Leukemia"},{"key":"8045_CR2","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1586\/14737140.2016.1151356","volume":"16","author":"F Stagno","year":"2016","unstructured":"Stagno F, Stella S, Spitaleri A, Pennisi MS, Di Raimondo F, Vigneri P. Imatinib mesylate in chronic myeloid leukemia: frontline treatment and long-term outcomes. Expert Rev Anticancer Ther. 2016;16:273\u20138.","journal-title":"Expert Rev Anticancer Ther"},{"key":"8045_CR3","doi-asserted-by":"publisher","first-page":"917","DOI":"10.1056\/NEJMoa1609324","volume":"376","author":"A Hochhaus","year":"2017","unstructured":"Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP, et al. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med. 2017;376:917\u201327.","journal-title":"N Engl J Med"},{"key":"8045_CR4","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1182\/blood-2014-03-566323","volume":"124","author":"S Branford","year":"2014","unstructured":"Branford S, Yeung DT, Parker WT, Roberts ND, Purins L, Braley JA, et al. Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline. Blood. 2014;124:511\u20138.","journal-title":"Blood"},{"key":"8045_CR5","doi-asserted-by":"publisher","first-page":"1141","DOI":"10.1182\/blood-2010-03-277152","volume":"117","author":"HM Kantarjian","year":"2011","unstructured":"Kantarjian HM, Giles FJ, Bhalla KN, Pinilla-Ibarz J, Larson RA, Gattermann N, et al. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood. 2011;117:1141\u20135.","journal-title":"Blood"},{"key":"8045_CR6","doi-asserted-by":"publisher","first-page":"1279","DOI":"10.3109\/10428194.2012.737919","volume":"54","author":"A Camgoz","year":"2013","unstructured":"Camgoz A, Gencer EB, Ural AU, Baran Y. Mechanisms responsible for nilotinib resistance in human chronic myeloid leukemia cells and reversal of resistance. Leuk Lymphoma. 2013;54:1279\u201387.","journal-title":"Leuk Lymphoma"},{"key":"8045_CR7","doi-asserted-by":"publisher","first-page":"2242","DOI":"10.1182\/blood-2007-03-066936","volume":"110","author":"T O\u2019Hare","year":"2007","unstructured":"O\u2019Hare T, Eide CA, Deininger MW. Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood. 2007;110:2242\u20139.","journal-title":"Blood"},{"key":"8045_CR8","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1016\/j.ccr.2009.09.028","volume":"16","author":"T O\u2019Hare","year":"2009","unstructured":"O\u2019Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009;16:401\u201312.","journal-title":"Cancer Cell"},{"key":"8045_CR9","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1038\/nrc3317","volume":"12","author":"T O\u2019Hare","year":"2012","unstructured":"O\u2019Hare T, Zabriskie MS, Eiring AM, Deininger MW. Pushing the limits of targeted therapy in chronic myeloid leukaemia. Nat Rev Cancer. 2012;12:513\u201326.","journal-title":"Nat Rev Cancer"},{"key":"8045_CR10","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1016\/j.ccr.2011.11.004","volume":"20","author":"LM Packer","year":"2011","unstructured":"Packer LM, Rana S, Hayward R, O\u2019Hare T, Eide CA, Rebocho A, et al. Nilotinib and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug-resistant chronic myeloid leukemia. Cancer Cell. 2011;20:715\u201327.","journal-title":"Cancer Cell"},{"key":"8045_CR11","doi-asserted-by":"publisher","first-page":"470","DOI":"10.5581\/1516-8484.20110124","volume":"33","author":"R Bitencourt","year":"2011","unstructured":"Bitencourt R, Zalcberg I, Louro ID. Imatinib resistance: a review of alternative inhibitors in chronic myeloid leukemia. Rev Bras Hematol Hemoter. 2011;33:470\u20135.","journal-title":"Rev Bras Hematol Hemoter"},{"key":"8045_CR12","doi-asserted-by":"publisher","first-page":"7519","DOI":"10.1158\/1078-0432.CCR-09-1068","volume":"15","author":"D Milojkovic","year":"2009","unstructured":"Milojkovic D, Apperley J. Mechanisms of resistance to imatinib and second-generation tyrosine inhibitors in chronic myeloid leukemia. Clin Cancer Res. 2009;15:7519\u201327.","journal-title":"Clin Cancer Res"},{"key":"8045_CR13","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1182\/blood-2012-05-431379","volume":"121","author":"JS Khorashad","year":"2013","unstructured":"Khorashad JS, Kelley TW, Szankasi P, Mason CC, Soverini S, Adrian LT, et al. BCR-ABL1 compound mutations in tyrosine kinase inhibitor-resistant CML: frequency and clonal relationships. Blood. 2013;121:489\u201398.","journal-title":"Blood"},{"key":"8045_CR14","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1016\/j.hoc.2017.04.007","volume":"31","author":"AB Patel","year":"2017","unstructured":"Patel AB, O\u2019Hare T, Deininger MW. Mechanisms of resistance to ABL kinase inhibition in chronic myeloid leukemia and the development of next generation ABL kinase inhibitors. Hematol Oncol Clin North Am. 2017;31:589\u2013612.","journal-title":"Hematol Oncol Clin North Am"},{"key":"8045_CR15","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1016\/j.celrep.2014.05.048","volume":"8","author":"S Schwartz","year":"2014","unstructured":"Schwartz S, Mumbach MR, Jovanovic M, Wang T, Maciag K, Bushkin GG, et al. Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5\u2019 sites. Cell Rep. 2014;8:284\u201396.","journal-title":"Cell Rep"},{"key":"8045_CR16","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1038\/nchembio.1432","volume":"10","author":"J Liu","year":"2014","unstructured":"Liu J, Yue Y, Han D, Wang X, Fu Y, Zhang L, et al. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol. 2014;10:93\u20135.","journal-title":"Nat Chem Biol"},{"key":"8045_CR17","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1038\/nchembio.687","volume":"7","author":"G Jia","year":"2011","unstructured":"Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol. 2011;7:885\u20137.","journal-title":"Nat Chem Biol"},{"key":"8045_CR18","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.molcel.2012.10.015","volume":"49","author":"G Zheng","year":"2013","unstructured":"Zheng G, Dahl JA, Niu Y, Fedorcsak P, Huang CM, Li CJ, et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell. 2013;49:18\u201329.","journal-title":"Mol Cell"},{"key":"8045_CR19","doi-asserted-by":"publisher","first-page":"1403","DOI":"10.1038\/cr.2014.151","volume":"24","author":"X Zhao","year":"2014","unstructured":"Zhao X, Yang Y, Sun BF, Shi Y, Yang X, Xiao W, et al. FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis. Cell Res. 2014;24:1403\u201319.","journal-title":"Cell Res"},{"key":"8045_CR20","doi-asserted-by":"publisher","first-page":"11356","DOI":"10.1093\/nar\/gkx778","volume":"45","author":"M Bartosovic","year":"2017","unstructured":"Bartosovic M, Molares HC, Gregorova P, Hrossova D, Kudla G, Vanacova S. N6-methyladenosine demethylase FTO targets pre-mRNAs and regulates alternative splicing and 3\u2019-end processing. Nucleic Acids Res. 2017;45:11356\u201370.","journal-title":"Nucleic Acids Res"},{"key":"8045_CR21","doi-asserted-by":"publisher","first-page":"2003","DOI":"10.1016\/j.molcel.2023.05.010","volume":"83","author":"F Yu","year":"2023","unstructured":"Yu F, Zhu AC, Liu S, Gao B, Wang Y, Khudaverdyan N, et al. RBM33 is a unique m(6)A RNA-binding protein that regulates ALKBH5 demethylase activity and substrate selectivity. Mol Cell. 2023;83:2003\u201319.e6.","journal-title":"Mol Cell"},{"key":"8045_CR22","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1038\/nature15377","volume":"526","author":"J Zhou","year":"2015","unstructured":"Zhou J, Wan J, Gao X, Zhang X, Jaffrey SR, Qian SB. Dynamic m(6)A mRNA methylation directs translational control of heat shock response. Nature. 2015;526:591\u20134.","journal-title":"Nature"},{"key":"8045_CR23","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1038\/nrg3724","volume":"15","author":"Y Fu","year":"2014","unstructured":"Fu Y, Dominissini D, Rechavi G, He C. Gene expression regulation mediated through reversible m(6)A RNA methylation. Nat Rev Genet. 2014;15:293\u2013306.","journal-title":"Nat Rev Genet"},{"key":"8045_CR24","doi-asserted-by":"publisher","first-page":"1412","DOI":"10.1093\/nar\/gkx1182","volume":"46","author":"J Yu","year":"2018","unstructured":"Yu J, Chen M, Huang H, Zhu J, Song H, Zhu J, et al. Dynamic m6A modification regulates local translation of mRNA in axons. Nucleic Acids Res. 2018;46:1412\u201323.","journal-title":"Nucleic Acids Res"},{"key":"8045_CR25","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/j.tig.2012.11.003","volume":"29","author":"G Jia","year":"2013","unstructured":"Jia G, Fu Y, He C. Reversible RNA adenosine methylation in biological regulation. Trends Genet. 2013;29:108\u201315.","journal-title":"Trends Genet"},{"key":"8045_CR26","doi-asserted-by":"publisher","first-page":"1343","DOI":"10.1101\/gad.262766.115","volume":"29","author":"Y Yue","year":"2015","unstructured":"Yue Y, Liu J, He C. RNA N6-methyladenosine methylation in post-transcriptional gene expression regulation. Genes Dev. 2015;29:1343\u201355.","journal-title":"Genes Dev"},{"key":"8045_CR27","doi-asserted-by":"publisher","first-page":"E325","DOI":"10.1073\/pnas.1717794115","volume":"115","author":"C Tang","year":"2018","unstructured":"Tang C, Klukovich R, Peng H, Wang Z, Yu T, Zhang Y, et al. ALKBH5-dependent m6A demethylation controls splicing and stability of long 3\u2019-UTR mRNAs in male germ cells. Proc Natl Acad Sci USA. 2018;115:E325\u201333.","journal-title":"Proc Natl Acad Sci USA"},{"key":"8045_CR28","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1038\/nature12730","volume":"505","author":"X Wang","year":"2014","unstructured":"Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 2014;505:117\u201320.","journal-title":"Nature"},{"key":"8045_CR29","doi-asserted-by":"publisher","first-page":"1187","DOI":"10.1016\/j.cell.2017.05.045","volume":"169","author":"IA Roundtree","year":"2017","unstructured":"Roundtree IA, Evans ME, Pan T, He C. Dynamic RNA modifications in gene expression regulation. Cell. 2017;169:1187\u2013200.","journal-title":"Cell"},{"key":"8045_CR30","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1038\/nature21355","volume":"542","author":"BS Zhao","year":"2017","unstructured":"Zhao BS, Wang X, Beadell AV, Lu Z, Shi H, Kuuspalu A, et al. m(6)A-dependent maternal mRNA clearance facilitates zebrafish maternal-to-zygotic transition. Nature. 2017;542:475\u20138.","journal-title":"Nature"},{"key":"8045_CR31","doi-asserted-by":"publisher","first-page":"1388","DOI":"10.1016\/j.cell.2015.05.014","volume":"161","author":"X Wang","year":"2015","unstructured":"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\u201399.","journal-title":"Cell"},{"key":"8045_CR32","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/j.ccell.2016.11.017","volume":"31","author":"Z Li","year":"2017","unstructured":"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\u201341.","journal-title":"Cancer Cell"},{"key":"8045_CR33","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1016\/j.ccell.2017.02.013","volume":"31","author":"S Zhang","year":"2017","unstructured":"Zhang S, Zhao BS, Zhou A, Lin K, Zheng S, Lu Z, et al. m(6)A Demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program. Cancer Cell. 2017;31:591\u2013606.e6.","journal-title":"Cancer Cell"},{"key":"8045_CR34","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.cell.2017.11.031","volume":"172","author":"R Su","year":"2018","unstructured":"Su R, Dong L, Li C, Nachtergaele S, Wunderlich M, Qing Y, et al. R-2HG exhibits anti-tumor activity by targeting FTO\/m(6)A\/MYC\/CEBPA signaling. Cell. 2018;172:90\u2013105.e23.","journal-title":"Cell"},{"key":"8045_CR35","doi-asserted-by":"publisher","first-page":"1074","DOI":"10.1038\/s41556-018-0174-4","volume":"20","author":"J Liu","year":"2018","unstructured":"Liu J, Eckert MA, Harada BT, Liu SM, Lu Z, Yu K, et al. m(6)A mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer. Nat Cell Biol. 2018;20:1074\u201383.","journal-title":"Nat Cell Biol"},{"key":"8045_CR36","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1038\/s41422-018-0034-6","volume":"28","author":"X Deng","year":"2018","unstructured":"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;28:507\u201317.","journal-title":"Cell Res"},{"key":"8045_CR37","doi-asserted-by":"publisher","first-page":"1062","DOI":"10.1038\/s41422-018-0097-4","volume":"28","author":"F Yan","year":"2018","unstructured":"Yan F, Al-Kali A, Zhang Z, Liu J, Pang J, Zhao N, et al. A dynamic N(6)-methyladenosine methylome regulates intrinsic and acquired resistance to tyrosine kinase inhibitors. Cell Res. 2018;28:1062\u201376.","journal-title":"Cell Res"},{"key":"8045_CR38","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/j.tig.2017.11.005","volume":"34","author":"Q Sun","year":"2018","unstructured":"Sun Q, Hao Q, Prasanth KV. Nuclear long noncoding RNAs: key regulators of gene expression. Trends Genet. 2018;34:142\u201357.","journal-title":"Trends Genet"},{"key":"8045_CR39","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.gpb.2015.09.006","volume":"14","author":"Y Fang","year":"2016","unstructured":"Fang Y, Fullwood MJ. Roles, functions, and mechanisms of long non-coding RNAs in cancer. Genom Proteom Bioinform. 2016;14:42\u201354.","journal-title":"Genom Proteom Bioinform"},{"key":"8045_CR40","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/j.molmed.2018.01.001","volume":"24","author":"G Arun","year":"2018","unstructured":"Arun G, Diermeier SD, Spector DL. Therapeutic targeting of long non-coding RNAs in cancer. Trends Mol Med. 2018;24:257\u201377.","journal-title":"Trends Mol Med"},{"key":"8045_CR41","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/j.ncrna.2018.03.001","volume":"3","author":"MM Balas","year":"2018","unstructured":"Balas MM, Johnson AM. Exploring the mechanisms behind long noncoding RNAs and cancer. Non-coding RNA Res. 2018;3:108\u201317.","journal-title":"Non-coding RNA Res"},{"key":"8045_CR42","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-018-0821-1","volume":"17","author":"KW Tsai","year":"2018","unstructured":"Tsai KW, Lo YH, Liu H, Yeh CY, Chen YZ, Hsu CW, et al. Linc00659, a long noncoding RNA, acts as novel oncogene in regulating cancer cell growth in colorectal cancer. Mol Cancer. 2018;17:72.","journal-title":"Mol Cancer"},{"key":"8045_CR43","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1002\/gcc.22691","volume":"58","author":"Y Li","year":"2019","unstructured":"Li Y, Egranov SD, Yang L, Lin C. Molecular mechanisms of long noncoding RNAs-mediated cancer metastasis. Genes, chromosomes cancer. 2019;58:200\u20137.","journal-title":"Genes, chromosomes cancer"},{"key":"8045_CR44","doi-asserted-by":"publisher","first-page":"1903","DOI":"10.3390\/ijms18091903","volume":"18","author":"HC Chi","year":"2017","unstructured":"Chi HC, Tsai CY, Tsai MM, Yeh CT, Lin KH. Roles of long noncoding RNAs in recurrence and metastasis of radiotherapy-resistant cancer stem cells. Int J Mol Sci. 2017;18:1903.","journal-title":"Int J Mol Sci"},{"key":"8045_CR45","doi-asserted-by":"publisher","first-page":"1705","DOI":"10.1038\/s41588-018-0252-3","volume":"50","author":"J Kim","year":"2018","unstructured":"Kim J, Piao HL, Kim BJ, Yao F, Han Z, Wang Y, et al. Long noncoding RNA MALAT1 suppresses breast cancer metastasis. Nat Genet. 2018;50:1705\u201315.","journal-title":"Nat Genet"},{"key":"8045_CR46","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-05495-9","volume":"9","author":"Y Wang","year":"2018","unstructured":"Wang Y, Wang Z, Xu J, Li J, Li S, Zhang M, et al. Systematic identification of non-coding pharmacogenomic landscape in cancer. Nat Commun. 2018;9:3192.","journal-title":"Nat Commun"},{"key":"8045_CR47","doi-asserted-by":"publisher","first-page":"8027","DOI":"10.18632\/oncotarget.2469","volume":"5","author":"E Malek","year":"2014","unstructured":"Malek E, Jagannathan S, Driscoll JJ. Correlation of long non-coding RNA expression with metastasis, drug resistance and clinical outcome in cancer. Oncotarget. 2014;5:8027\u201338.","journal-title":"Oncotarget"},{"key":"8045_CR48","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1038\/nature19342","volume":"537","author":"DP Patil","year":"2016","unstructured":"Patil DP, Chen CK, Pickering BF, Chow A, Jackson C, Guttman M, et al. m(6)A RNA methylation promotes XIST-mediated transcriptional repression. Nature. 2016;537:369\u201373.","journal-title":"Nature"},{"key":"8045_CR49","doi-asserted-by":"publisher","first-page":"562","DOI":"10.1016\/j.celrep.2015.06.053","volume":"12","author":"B Moindrot","year":"2015","unstructured":"Moindrot B, Cerase A, Coker H, Masui O, Grijzenhout A, Pintacuda G, et al. A pooled shRNA screen identifies Rbm15, Spen, and Wtap as factors required for Xist RNA-mediated silencing. Cell Rep. 2015;12:562\u201372.","journal-title":"Cell Rep"},{"key":"8045_CR50","doi-asserted-by":"publisher","first-page":"1253","DOI":"10.1038\/nm.3981","volume":"21","author":"M Huarte","year":"2015","unstructured":"Huarte M. The emerging role of lncRNAs in cancer. Nat Med. 2015;21:1253\u201361.","journal-title":"Nat Med"},{"key":"8045_CR51","doi-asserted-by":"publisher","first-page":"12181","DOI":"10.1007\/s13277-014-2526-4","volume":"35","author":"X He","year":"2014","unstructured":"He X, Tan X, Wang X, Jin H, Liu L, Ma L, et al. C-Myc-activated long noncoding RNA CCAT1 promotes colon cancer cell proliferation and invasion. Tumor Biol. 2014;35:12181\u20138.","journal-title":"Tumor Biol"},{"key":"8045_CR52","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1158\/1535-7163.MCT-14-0492","volume":"14","author":"FQ Nie","year":"2015","unstructured":"Nie FQ, Sun M, Yang JS, Xie M, Xu TP, Xia R, et al. Long noncoding RNA ANRIL promotes non-small cell lung cancer cell proliferation and inhibits apoptosis by silencing KLF2 and P21 expression. Mol Cancer Ther. 2015;14:268\u201377.","journal-title":"Mol Cancer Ther"},{"key":"8045_CR53","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12960-6","volume":"10","author":"L Dou","year":"2019","unstructured":"Dou L, Yan F, Pang J, Zheng D, Li D, Gao L, et al. Protein lysine 43 methylation by EZH1 promotes AML1-ETO transcriptional repression in leukemia. Nat Commun. 2019;10:5051.","journal-title":"Nat Commun"},{"key":"8045_CR54","doi-asserted-by":"publisher","first-page":"1434","DOI":"10.1038\/leu.2016.349","volume":"31","author":"F Yan","year":"2017","unstructured":"Yan F, Shen N, Pang JX, Zhang YW, Rao EY, Bode AM, et al. Fatty acid-binding protein FABP4 mechanistically links obesity with aggressive AML by enhancing aberrant DNA methylation in AML cells. Leukemia. 2017;31:1434\u201342.","journal-title":"Leukemia"},{"key":"8045_CR55","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1038\/nmeth.3317","volume":"12","author":"D Kim","year":"2015","unstructured":"Kim D, Langmead B, Salzberg SL. HISAT: a fast spliced aligner with low memory requirements. Nat Methods. 2015;12:357\u201360.","journal-title":"Nat Methods"},{"key":"8045_CR56","doi-asserted-by":"publisher","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","volume":"25","author":"H Li","year":"2009","unstructured":"Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The sequence alignment\/map format and SAMtools. Bioinformatics. 2009;25:2078\u20139.","journal-title":"Bioinformatics"},{"key":"8045_CR57","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","volume":"30","author":"Y Liao","year":"2014","unstructured":"Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30:923\u201330.","journal-title":"Bioinformatics"},{"key":"8045_CR58","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","volume":"26","author":"MD Robinson","year":"2010","unstructured":"Robinson MD, McCarthy DJ, Smyth GK. edgeR: a bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26:139\u201340.","journal-title":"Bioinformatics"},{"key":"8045_CR59","doi-asserted-by":"publisher","first-page":"e47","DOI":"10.1093\/nar\/gkv007","volume":"43","author":"ME Ritchie","year":"2015","unstructured":"Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43:e47.","journal-title":"Nucleic Acids Res"},{"key":"8045_CR60","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1182\/blood.2022016867","volume":"140","author":"H Dohner","year":"2022","unstructured":"Dohner 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\u201377.","journal-title":"Blood"},{"key":"8045_CR61","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2011-12-2-r16","volume":"12","author":"L Yang","year":"2011","unstructured":"Yang L, Duff MO, Graveley BR, Carmichael GG, Chen LL. Genomewide characterization of non-polyadenylated RNAs. Genome Biol. 2011;12:R16.","journal-title":"Genome Biol"},{"key":"8045_CR62","doi-asserted-by":"publisher","first-page":"984","DOI":"10.6004\/jnccn.2009.0065","volume":"7","author":"S O\u2019Brien","year":"2009","unstructured":"O\u2019Brien S, Berman E, Borghaei H, Deangelo DJ, Devetten MP, Devine S, et al. NCCN clinical practice guidelines in oncology: chronic myelogenous leukemia. J Natl Compr Cancer Netw. 2009;7:984\u20131023.","journal-title":"J Natl Compr Cancer Netw"},{"key":"8045_CR63","doi-asserted-by":"publisher","first-page":"W98","DOI":"10.1093\/nar\/gkx247","volume":"45","author":"Z Tang","year":"2017","unstructured":"Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45:W98\u2013102.","journal-title":"Nucleic Acids Res"},{"key":"8045_CR64","doi-asserted-by":"publisher","first-page":"D917","DOI":"10.1093\/nar\/gkv1101","volume":"44","author":"FO Bagger","year":"2016","unstructured":"Bagger FO, Sasivarevic D, Sohi SH, Laursen LG, Pundhir S, Sonderby CK, et al. BloodSpot: a database of gene expression profiles and transcriptional programs for healthy and malignant haematopoiesis. Nucleic Acids Res. 2016;44:D917\u201324.","journal-title":"Nucleic Acids Res"},{"key":"8045_CR65","doi-asserted-by":"publisher","first-page":"1002","DOI":"10.1126\/science.1261417","volume":"347","author":"S Geula","year":"2015","unstructured":"Geula S, Moshitch-Moshkovitz S, Dominissini D, Mansour AA, Kol N, Salmon-Divon M, et al. m6A mRNA methylation facilitates resolution of naive pluripotency toward differentiation. Science. 2015;347:1002\u20136.","journal-title":"Science"},{"key":"8045_CR66","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1093\/nar\/gku1276","volume":"43","author":"Y Huang","year":"2015","unstructured":"Huang Y, Yan J, Li Q, Li J, Gong S, Zhou H, et al. Meclofenamic acid selectively inhibits FTO demethylation of m6A over ALKBH5. Nucleic Acids Res. 2015;43:373\u201384.","journal-title":"Nucleic Acids Res"},{"key":"8045_CR67","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1016\/j.ccell.2019.03.006","volume":"35","author":"Y Huang","year":"2019","unstructured":"Huang Y, Su R, Sheng Y, Dong L, Dong Z, Xu H, et al. Small-molecule targeting of oncogenic FTO demethylase in acute myeloid leukemia. Cancer Cell. 2019;35:677\u201391 e610.","journal-title":"Cancer Cell"},{"key":"8045_CR68","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1038\/leu.2012.222","volume":"27","author":"FU Wohrle","year":"2013","unstructured":"Wohrle FU, Halbach S, Aumann K, Schwemmers S, Braun S, Auberger P, et al. Gab2 signaling in chronic myeloid leukemia cells confers resistance to multiple Bcr-Abl inhibitors. Leukemia. 2013;27:118\u201329.","journal-title":"Leukemia"},{"key":"8045_CR69","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1038\/sj.leu.2404523","volume":"21","author":"PL Tazzari","year":"2007","unstructured":"Tazzari PL, Cappellini A, Ricci F, Evangelisti C, Papa V, Grafone T, et al. Multidrug resistance-associated protein 1 expression is under the control of the phosphoinositide 3 kinase\/Akt signal transduction network in human acute myelogenous leukemia blasts. Leukemia. 2007;21:427\u201338.","journal-title":"Leukemia"},{"key":"8045_CR70","doi-asserted-by":"publisher","first-page":"6254","DOI":"10.1158\/1078-0432.CCR-17-0235","volume":"23","author":"N Shen","year":"2017","unstructured":"Shen N, Yan F, Pang J, Zhao N, Gangat N, Wu L, et al. Inactivation of receptor tyrosine kinases reverts aberrant DNA methylation in acute myeloid leukemia. Clin Cancer Res. 2017;23:6254\u201366.","journal-title":"Clin Cancer Res"},{"key":"8045_CR71","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1182\/blood-2009-03-210732","volume":"115","author":"SK McWeeney","year":"2010","unstructured":"McWeeney SK, Pemberton LC, Loriaux MM, Vartanian K, Willis SG, Yochum G, et al. A gene expression signature of CD34+ cells to predict major cytogenetic response in chronic-phase chronic myeloid leukemia patients treated with imatinib. Blood. 2010;115:315\u201325.","journal-title":"Blood"},{"key":"8045_CR72","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abg0809","volume":"13","author":"F Delestre","year":"2021","unstructured":"Delestre F, Venot Q, Bayard C, Fraissenon A, Ladraa S, Hoguin C, et al. Alpelisib administration reduced lymphatic malformations in a mouse model and in patients. Sci Transl Med. 2021;13:eabg0809.","journal-title":"Sci Transl Med"},{"key":"8045_CR73","doi-asserted-by":"publisher","first-page":"11011","DOI":"10.1073\/pnas.0504952102","volume":"102","author":"TA Carter","year":"2005","unstructured":"Carter TA, Wodicka LM, Shah NP, Velasco AM, Fabian MA, Treiber DK, et al. Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. Proc Natl Acad Sci USA. 2005;102:11011\u20136.","journal-title":"Proc Natl Acad Sci USA"},{"key":"8045_CR74","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1016\/j.molcel.2014.05.015","volume":"54","author":"H Easwaran","year":"2014","unstructured":"Easwaran H, Tsai HC, Baylin SB. Cancer epigenetics: tumor heterogeneity, plasticity of stem-like states, and drug resistance. Mol Cell. 2014;54:716\u201327.","journal-title":"Mol Cell"},{"key":"8045_CR75","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1016\/j.ccell.2016.03.009","volume":"29","author":"T Mazor","year":"2016","unstructured":"Mazor T, Pankov A, Song JS, Costello JF. Intratumoral heterogeneity of the epigenome. Cancer Cell. 2016;29:440\u201351.","journal-title":"Cancer Cell"},{"key":"8045_CR76","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/j.semcancer.2017.07.006","volume":"51","author":"S Koschmieder","year":"2018","unstructured":"Koschmieder S, Vetrie D. Epigenetic dysregulation in chronic myeloid leukaemia: a myriad of mechanisms and therapeutic options. Semin Cancer Biol. 2018;51:180\u201397.","journal-title":"Semin Cancer Biol"},{"key":"8045_CR77","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1016\/j.cell.2018.03.052","volume":"173","author":"AC Bester","year":"2018","unstructured":"Bester AC, Lee JD, Chavez A, Lee YR, Nachmani D, Vora S, et al. An integrated genome-wide CRISPRa approach to functionalize lncRNAs in drug resistance. Cell. 2018;173:649\u201364.e20.","journal-title":"Cell"},{"key":"8045_CR78","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2013.309","volume":"4","author":"K Airiau","year":"2013","unstructured":"Airiau K, Mahon FX, Josselin M, Jeanneteau M, Belloc F. PI3K\/mTOR pathway inhibitors sensitize chronic myeloid leukemia stem cells to nilotinib and restore the response of progenitors to nilotinib in the presence of stem cell factor. Cell Death Dis. 2013;4:e827.","journal-title":"Cell Death Dis"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08045-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08045-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08045-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T14:03:11Z","timestamp":1762524191000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08045-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,7]]},"references-count":78,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["8045"],"URL":"https:\/\/doi.org\/10.1038\/s41419-025-08045-6","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,7]]},"assertion":[{"value":"17 February 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 August 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 September 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 November 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All patients gave their written informed consent for scientific evaluations. The current study was approved by the Institutional Review Board of Mayo Clinic and the second hospital of Shanxi Medical University and conducted in accordance with the Declaration of Helsinki. All animal experiments were approved by the Institutional Animal Care and Use Committees of the University of Minnesota and were in accordance with the U.S. National Institutes of Health (NIH) Guide for Care and Use of Laboratory Animals.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}],"article-number":"804"}}