{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T10:29:10Z","timestamp":1794047350081,"version":"4.8.0"},"reference-count":61,"publisher":"Ferrata Storti Foundation (Haematologica)","issue":"1","license":[{"start":{"date-parts":[[2020,1,9]],"date-time":"2020-01-09T00:00:00Z","timestamp":1578528000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/legalcode"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["haematol"],"abstract":"<jats:p>Retrotransposons such as LINE-1 and Alu comprise &gt;25% of the human genome. While global hypomethylation of these elements has been widely reported in solid tumours, their epigenetic dysregulation is yet to be characterised in chronic lymphocytic leukaemia, and there has been scant consideration of their evolutionary history that mediates sensitivity to hypomethylation. Here, we developed an approach for locus- and evolutionary subfamily-specific analysis of retrotransposons using the Illumina Infinium Human Methylation 450K microarray platform, which we applied to publicly-available datasets from chronic lymphocytic leukaemia and other haematological malignancies. We identified 9,797 microarray probes mapping to 117 LINE-1 subfamilies and 13,130 mapping to 37 Alu subfamilies. Of these, 10,782 were differentially methylated (PFDR&lt;0.05) in chronic lymphocytic leukaemia patients (n=139) compared with healthy individuals (n=14), with enrichment at enhancers (p=0.002). Differential methylation was associated with evolutionary age of LINE-1 (r2=0.31, p=0.003) and Alu (r2=0.74, p=0.002) elements, with greater hypomethylation of older subfamilies (L1M, AluJ). Locus-specific hypomethylation was associated with differential expression of proximal genes, including DCLK2, HK1, ILRUN, TANK, TBCD, TNFRSF1B and TXNRD2, with higher expression of DCLK2 and TNFRSF1B associated with reduced patient survival. Hypomethylation at nine loci was highly frequent in chronic lymphocytic leukaemia (&gt;90% patients) but not observed in healthy individuals or other leukaemias, and was detectable in blood samples taken prior to chronic lymphocytic leukaemia diagnosis in 9 of 82 individuals from the Melbourne Collaborative Cohort Study. Our results demonstrate differential methylation of retrotransposons in chronic lymphocytic leukaemia by their evolutionary heritage that modulates expression of proximal genes.<\/jats:p>","DOI":"10.3324\/haematol.2019.228478","type":"journal-article","created":{"date-parts":[[2020,1,9]],"date-time":"2020-01-09T12:14:28Z","timestamp":1578572068000},"page":"98-110","source":"Crossref","is-referenced-by-count":17,"title":["Analysis of retrotransposon subfamily DNA methylation reveals novel early epigenetic changes in chronic lymphocytic leukemia"],"prefix":"10.3324","volume":"106","author":[{"given":"Timothy M.","family":"Barrow","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Wong Doo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger L.","family":"Milne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham G.","family":"Giles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine","family":"Willmore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordon","family":"Strathdee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyang-Min","family":"Byun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1856","published-online":{"date-parts":[[2020,1,9]]},"reference":[{"key":"17443","doi-asserted-by":"crossref","unstructured":"Mighell AJ, Markham AF, Robinson PA. Alu sequences. FEBS Lett. 1997; 417(1):1-5.","DOI":"10.1016\/S0014-5793(97)01259-3"},{"key":"17444","doi-asserted-by":"crossref","unstructured":"Price AL, Eskin E, Pevzner PA. Wholegenome analysis of Alu repeat elements reveals complex evolutionary history. Genome Res. 2004; 14(11):2245-2252.","DOI":"10.1101\/gr.2693004"},{"key":"17445","doi-asserted-by":"crossref","unstructured":"Mills RE, Bennett EA, Iskow RC, Devine SE. Which transposable elements are active in the human genome?. Trends Genet. 2007; 23(4):183-191.","DOI":"10.1016\/j.tig.2007.02.006"},{"key":"17446","unstructured":"Konkel MK, Walker JA, Hotard AB. Sequence analysis and characterization of active human Alu subfamilies based on the 1000 Genomes Pilot Project. Genome Biol Evol. 2015; 7(9):2608-2622."},{"key":"17447","doi-asserted-by":"crossref","unstructured":"Beck CR, Collier P, Macfarlane C. LINE-1 retrotransposition activity in human genomes. Cell. 2010; 141(7):1159-1170.","DOI":"10.1016\/j.cell.2010.05.021"},{"key":"17448","doi-asserted-by":"crossref","unstructured":"Xing J, Zhang Y, Han K. Mobile elements create structural variation: analysis of a complete human genome. Genome Res. 2009; 19(9):1516-1526.","DOI":"10.1101\/gr.091827.109"},{"key":"17449","doi-asserted-by":"crossref","unstructured":"Bollati V, Baccarelli A, Hou L. Changes in DNA methylation patterns in subjects exposed to low-dose benzene. Cancer Res. 2007; 67(3):876-880.","DOI":"10.1158\/0008-5472.CAN-06-2995"},{"key":"17450","doi-asserted-by":"crossref","unstructured":"Breton CV, Byun HM, Wenten M, Pan F, Yang A, Gilliland FD. Prenatal tobacco smoke exposure affects global and gene-specific DNA methylation. Am J Respir Crit Care Med. 2009; 180(5):462-467.","DOI":"10.1164\/rccm.200901-0135OC"},{"key":"17451","doi-asserted-by":"crossref","unstructured":"Byun HM, Motta V, Panni T. Evolutionary age of repetitive element subfamilies and sensitivity of DNA methylation to airborne pollutants. Part Fibre Toxicol. 2013; 10:28.","DOI":"10.1186\/1743-8977-10-28"},{"key":"17452","doi-asserted-by":"crossref","unstructured":"Xiao-Jie L, Hui-Ying X, Qi X, Jiang X, Shi-Jie M. LINE-1 in cancer: multifaceted functions and potential clinical implications. Genet Med. 2016; 18(5):431-439.","DOI":"10.1038\/gim.2015.119"},{"key":"17453","doi-asserted-by":"crossref","unstructured":"Benard A, van de Velde CJ, Lessard L. Epigenetic status of LINE-1 predicts clinical outcome in early-stage rectal cancer. Br J Cancer. 2013; 109(12):3073-3083.","DOI":"10.1038\/bjc.2013.654"},{"key":"17454","doi-asserted-by":"crossref","unstructured":"Wolff EM, Byun HM, Han HF. Hypomethylation of a LINE-1 promoter activates an alternate transcript of the MET oncogene in bladders with cancer. PLoS Genet. 2010; 6(4):e1000917.","DOI":"10.1371\/journal.pgen.1000917"},{"key":"17455","doi-asserted-by":"crossref","unstructured":"Daskalos A, Nikolaidis G, Xinarianos G. Hypomethylation of retrotransposable elements correlates with genomic instability in non-small cell lung cancer. Int J Cancer. 2009; 124(1):81-87.","DOI":"10.1002\/ijc.23849"},{"key":"17456","doi-asserted-by":"crossref","unstructured":"Symer DE, Connelly C, Szak ST. Human L1 retrotransposition is associated with genetic instability in vivo. Cell. 2002; 110(3):327-338.","DOI":"10.1016\/S0092-8674(02)00839-5"},{"key":"17457","doi-asserted-by":"crossref","unstructured":"Tubio JMC, Li Y, Ju YS. Mobile DNA in cancer. Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes. Science. 2014; 345(6196):1251343.","DOI":"10.1126\/science.1251343"},{"key":"17458","doi-asserted-by":"crossref","unstructured":"Lee E, Iskow R, Yang L. Landscape of somatic retrotransposition in human cancers. Science. 2012; 337(6097):967-971.","DOI":"10.1126\/science.1222077"},{"key":"17459","doi-asserted-by":"crossref","unstructured":"Scott EC, Gardner EJ, Masood A, Chuang NT, Vertino PM, Devine SE. A hot L1 retrotransposon evades somatic repression and initiates human colorectal cancer. Genome Res. 2016; 26(6):745-755.","DOI":"10.1101\/gr.201814.115"},{"key":"17460","doi-asserted-by":"crossref","unstructured":"Ewing AD, Gacita A, Wood LD. Widespread somatic L1 retrotransposition occurs early during gastrointestinal cancer evolution. Genome Res. 2015; 25(10):1536-1545.","DOI":"10.1101\/gr.196238.115"},{"key":"17461","doi-asserted-by":"crossref","unstructured":"Doucet-O\u2019Hare TT, Rodi\u0107 N, Sharma R. LINE-1 expression and retrotransposition in Barrett\u2019s esophagus and esophageal carcinoma. Proc Natl Acad Sci U S A. 2015; 112(35):E4894-4900.","DOI":"10.1073\/pnas.1502474112"},{"key":"17462","doi-asserted-by":"crossref","unstructured":"Kulis M, Heath S, Bibikova M. Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia. Nat Genet. 2012; 44(11):1236-1242.","DOI":"10.1038\/ng.2443"},{"key":"17463","doi-asserted-by":"crossref","unstructured":"Oakes CC, Claus R, Gu L. Evolution of DNA methylation is linked to genetic aberrations in chronic lymphocytic leukemia. Cancer Discov. 2014; 4(3):348-361.","DOI":"10.1158\/2159-8290.CD-13-0349"},{"key":"17464","doi-asserted-by":"crossref","unstructured":"Fabris S, Bollati V, Agnelli L. Biological and clinical relevance of quantitative global methylation of repetitive DNA sequences in chronic lymphocytic leukemia. Epigenetics. 2011; 6(2):188-194.","DOI":"10.4161\/epi.6.2.13528"},{"key":"17465","doi-asserted-by":"crossref","unstructured":"Hoxha M, Fabris S, Agnelli L. Relevance of telomere\/telomerase system impairment in early stage chronic lymphocytic leukemia. Genes Chromosomes Cancer. 2014; 53(7):612-621.","DOI":"10.1002\/gcc.22171"},{"key":"17466","doi-asserted-by":"crossref","unstructured":"Hannum G, Guinney J, Zhao L. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell. 2013; 49(2):359-367.","DOI":"10.1016\/j.molcel.2012.10.016"},{"key":"17467","doi-asserted-by":"crossref","unstructured":"Demetriou CA, Chen J, Polidoro S. Methylome analysis and epigenetic changes associated with menarcheal age. PLoS One. 2013; 8(11):e79391.","DOI":"10.1371\/journal.pone.0079391"},{"key":"17468","doi-asserted-by":"crossref","unstructured":"Kananen L, Marttila S, Nevalainen T. Aging-associated DNA methylation changes in middle-aged individuals: the Young Finns study. BMC Genomics. 2016; 17:103.","DOI":"10.1186\/s12864-016-2421-z"},{"key":"17469","doi-asserted-by":"crossref","unstructured":"Nordlund J, B\u00e4cklin CL, Wahlberg P. Genome-wide signatures of differential DNA methylation in pediatric acute lymphoblastic leukemia. Genome Biol. 2013; 14(9):r105.","DOI":"10.1186\/gb-2013-14-9-r105"},{"key":"17470","doi-asserted-by":"crossref","unstructured":"Maupetit-Mehouas S, Court F, Bourgne C. DNA methylation profiling reveals a pathological signature that contributes to transcriptional defects of CD34. Mol Oncol. 2018; 12(6):814-829.","DOI":"10.1002\/1878-0261.12191"},{"key":"17471","doi-asserted-by":"crossref","unstructured":"Ferreira HJ, Heyn H, Vizoso M. DNMT3A mutations mediate the epigenetic reactivation of the leukemogenic factor MEIS1 in acute myeloid leukemia. Oncogene. 2016; 35(23):3079-3082.","DOI":"10.1038\/onc.2015.359"},{"key":"17472","doi-asserted-by":"crossref","unstructured":"Matsunaga A, Hishima T, Tanaka N. DNA methylation profiling can classify HIVassociated lymphomas. AIDS. 2014; 28(4):503-510.","DOI":"10.1097\/QAD.0000000000000120"},{"key":"17473","doi-asserted-by":"crossref","unstructured":"Reinius LE, Acevedo N, Joerink M. Differential DNA methylation in purified human blood cells: implications for cell lineage and studies on disease susceptibility. PLoS One. 2012;7e41361.","DOI":"10.1371\/journal.pone.0041361"},{"key":"17474","doi-asserted-by":"crossref","unstructured":"Lee ST, Xiao Y, Muench MO. A global DNA methylation and gene expression analysis of early human B-cell development reveals a demethylation signature and transcription factor network. Nucleic Acids Res. 2012; 40(22):11339-11351.","DOI":"10.1093\/nar\/gks957"},{"key":"17475","doi-asserted-by":"crossref","unstructured":"Wong Doo N, Makalic E, Joo JE. Global measures of peripheral blood-derived DNA methylation as a risk factor in the development of mature B-cell neoplasms. Epigenomics. 2016; 8(1):55-66.","DOI":"10.2217\/epi.15.97"},{"key":"17476","doi-asserted-by":"crossref","unstructured":"Kent WJ, Sugnet CW, Furey TS. The human genome browser at UCSC. Genome Res. 2002; 12(6):996-1006.","DOI":"10.1101\/gr.229102"},{"key":"17477","unstructured":"Smit AFA, Hubley R, Green P. RepeatMasker Open-4.0. 2013."},{"key":"17478","doi-asserted-by":"crossref","unstructured":"Kapitonov V, Jurka J. The age of Alu subfamilies. J Mol Evol. 1996; 42(1):59-65.","DOI":"10.1007\/BF00163212"},{"key":"17479","doi-asserted-by":"crossref","unstructured":"Khan H, Smit A, Boissinot S. Molecular evolution and tempo of amplification of human LINE-1 retrotransposons since the origin of primates. Genome Res. 2006; 16(1):78-87.","DOI":"10.1101\/gr.4001406"},{"key":"17480","doi-asserted-by":"crossref","unstructured":"Houseman EA, Accomando WP, Koestler DC. DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinformatics. 2012; 13:86.","DOI":"10.1186\/1471-2105-13-86"},{"key":"17481","doi-asserted-by":"crossref","unstructured":"Price EM, Cotton AM, Pe\u00f1aherrera MS, McFadden DE, Kobor MS, Robinson W. Different measures of \u201cgenome-wide\u201d DNA methylation exhibit unique properties in placental and somatic tissues. Epigenetics. 2012; 7(6):652-663.","DOI":"10.4161\/epi.20221"},{"key":"17482","doi-asserted-by":"crossref","unstructured":"Zheng Y, Joyce BT, Liu L. Prediction of genome-wide DNA methylation in repetitive elements. Nucleic Acids Res. 2017; 45(15):8697-8711.","DOI":"10.1093\/nar\/gkx587"},{"key":"17483","doi-asserted-by":"crossref","unstructured":"Landau DA, Clement K, Ziller MJ. Locally disordered methylation forms the basis of intratumor methylome variation in chronic lymphocytic leukemia. Cancer Cell. 2014; 26(6):813-825.","DOI":"10.1016\/j.ccell.2014.10.012"},{"key":"17484","doi-asserted-by":"crossref","unstructured":"Strefford JC, Kadalayil L, Forster J. Telomere length predicts progression and overall survival in chronic lymphocytic leukemia: data from the UK LRF CLL4 trial. Leukemia. 2015; 29(12):2411-2414.","DOI":"10.1038\/leu.2015.217"},{"key":"17485","doi-asserted-by":"crossref","unstructured":"Keane TM, Wong K, Adams DJ. RetroSeq: transposable element discovery from nextgeneration sequencing data. Bioinformatics. 2013; 29(3):389-390.","DOI":"10.1093\/bioinformatics\/bts697"},{"key":"17486","doi-asserted-by":"crossref","unstructured":"Hui D, Satkunam N, Al Kaptan M, Reiman T, Lai R. Pathway-specific apoptotic gene expression profiling in chronic lymphocytic leukemia and follicular lymphoma. Mod Pathol. 2006; 19(9):1192-1202.","DOI":"10.1038\/modpathol.3800632"},{"key":"17487","doi-asserted-by":"crossref","unstructured":"Wang J, Coombes KR, Highsmith WE, Keating MJ, Abruzzo LV. Differences in gene expression between B-cell chronic lymphocytic leukemia and normal B cells: a metaanalysis of three microarray studies. Bioinformatics. 2004; 20(17):3166-3178.","DOI":"10.1093\/bioinformatics\/bth381"},{"key":"17488","doi-asserted-by":"crossref","unstructured":"Laurenzana A, Petruccelli LA, Pettersson F. Inhibition of DNA methyltransferase activates tumor necrosis factor alphainduced monocytic differentiation in acute myeloid leukemia cells. Cancer Res. 2009; 69(1):55-64.","DOI":"10.1158\/0008-5472.CAN-08-0245"},{"key":"17489","doi-asserted-by":"crossref","unstructured":"McGuire MH, Herbrich SM, Dasari SK. Pan-cancer genomic analysis links 3\u2019UTR DNA methylation with increased gene expression in T cells. EBioMedicine. 2019; 43:127-137.","DOI":"10.1016\/j.ebiom.2019.04.045"},{"key":"17490","doi-asserted-by":"crossref","unstructured":"Baud V, Karin M. Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol. 2001; 11(9):372-377.","DOI":"10.1016\/S0962-8924(01)02064-5"},{"key":"17491","doi-asserted-by":"crossref","unstructured":"Dai J, Li ZX, Zhang Y. Whole genome messenger RNA profiling identifies a novel signature to predict gastric cancer survival. Clin Transl Gastroenterol. 2019; 10(1):e00004.","DOI":"10.14309\/ctg.0000000000000004"},{"key":"17492","doi-asserted-by":"crossref","unstructured":"Gao T, Wang M, Xu L, Wen T, Liu J, An G. DCLK1 is up-regulated and associated with metastasis and prognosis in colorectal cancer. J Cancer Res Clin Oncol. 2016; 142(10):2131-2140.","DOI":"10.1007\/s00432-016-2218-0"},{"key":"17493","doi-asserted-by":"crossref","unstructured":"Mosquera Orgueira A, Antelo Rodr\u00edguez B, Alonso Vence N. The association of germline variants with chronic lymphocytic leukemia outcome suggests the implication of novel genes and pathways in clinical evolution. BMC Cancer. 2019; 19(1):515.","DOI":"10.1186\/s12885-019-5628-y"},{"key":"17494","unstructured":"Lincoln DT, Ali Emadi EM, Tonissen KF, Clarke FM. The thioredoxin-thioredoxin reductase system: over-expression in human cancer. Anticancer Res. 2003; 23(3B):2425-2433."},{"key":"17495","doi-asserted-by":"crossref","unstructured":"Fiskus W, Saba N, Shen M. Auranofin induces lethal oxidative and endoplasmic reticulum stress and exerts potent preclinical activity against chronic lymphocytic leukemia. Cancer Res. 2014; 74(9):2520-2532.","DOI":"10.1158\/0008-5472.CAN-13-2033"},{"key":"17496","doi-asserted-by":"crossref","unstructured":"Ferreira PG, Jares P, Rico D. Transcriptome characterization by RNA sequencing identifies a major molecular and clinical subdivision in chronic lymphocytic leukemia. Genome Res. 2014; 24(2):212-226.","DOI":"10.1101\/gr.152132.112"},{"key":"17497","doi-asserted-by":"crossref","unstructured":"Schulz WA, Steinhoff C, Florl AR. Methylation of endogenous human retroelements in health and disease. Curr Top Microbiol Immunol. 2006; 310:211-250.","DOI":"10.1007\/3-540-31181-5_11"},{"key":"17498","doi-asserted-by":"crossref","unstructured":"Baliakas P, Hadzidimitriou A, Sutton LA. Recurrent mutations refine prognosis in chronic lymphocytic leukemia. Leukemia. 2015; 29(2):329-336.","DOI":"10.1038\/leu.2014.196"},{"key":"17499","doi-asserted-by":"crossref","unstructured":"Landau DA, Tausch E, Taylor-Weiner AN. Mutations driving CLL and their evolution in progression and relapse. Nature. 2015; 526(7574):525-530.","DOI":"10.1038\/nature15395"},{"key":"17500","doi-asserted-by":"crossref","unstructured":"Puente XS, Be\u00e0 S, Vald\u00e9s-Mas R. Noncoding recurrent mutations in chronic lymphocytic leukaemia. Nature. 2015; 526(7574):519-524.","DOI":"10.1038\/nature14666"},{"key":"17501","doi-asserted-by":"crossref","unstructured":"Berndt SI, Skibola CF, Joseph V. Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia. Nat Genet. 2013; 45(8):868-876.","DOI":"10.1038\/ng.2652"},{"key":"17502","doi-asserted-by":"crossref","unstructured":"Law PJ, Berndt SI, Speedy HE. Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia. Nat Commun. 2017; 8:14175.","DOI":"10.1038\/ncomms14175"},{"key":"17503","doi-asserted-by":"crossref","unstructured":"Ng SK, Xue H. Alu-associated enhancement of single nucleotide polymorphisms in the human genome. Gene. 2006; 368:110-116.","DOI":"10.1016\/j.gene.2005.10.034"}],"container-title":["Haematologica"],"original-title":[],"link":[{"URL":"https:\/\/haematologica.org\/article\/download\/9594\/70403","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/haematologica.org\/article\/download\/9594\/70404","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/haematologica.org\/article\/download\/9594\/70403","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T09:55:43Z","timestamp":1794045343000},"score":1,"resource":{"primary":{"URL":"https:\/\/haematologica.org\/article\/view\/9594"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,9]]},"references-count":61,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12,31]]}},"URL":"https:\/\/doi.org\/10.3324\/haematol.2019.228478","relation":{},"ISSN":["1592-8721","0390-6078"],"issn-type":[{"value":"1592-8721","type":"electronic"},{"value":"0390-6078","type":"print"}],"subject":[],"published":{"date-parts":[[2020,1,9]]}}}