{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:11:51Z","timestamp":1792789911388,"version":"4.5.0"},"reference-count":44,"publisher":"National Academy of Sciences","issue":"32","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,8,11]]},"abstract":"<jats:p>\n                    Epigenetic alterations, including gain or loss of DNA methylation, are a hallmark of nearly every malignancy. Changes in DNA methylation can impact expression of cancer-related genes including apoptosis regulators and tumor suppressors. Because such epigenetic changes are reversible, they are being aggressively investigated as potential therapeutic targets. Here we use the E\u03bc-TCL1 transgenic mouse model of chronic lymphocytic leukemia (CLL) to determine the timing and patterns of aberrant DNA methylation, and to investigate the mechanisms that lead to aberrant DNA methylation. We show that CLL cells from E\u03bc-TCL1 mice at various stages recapitulate epigenetic alterations seen in human CLL. Aberrant methylation of promoter sequences is observed as early as 3 months of age in these animals, well before disease onset. Abnormally methylated promoter regions include binding sites for the transcription factor FOXD3. We show that loss of\n                    <jats:italic>Foxd3<\/jats:italic>\n                    expression due to an NF-\u03baB p50\/p50:HDAC1 repressor complex occurs in TCL1-positive B cells before methylation. Therefore, specific transcriptional repression is an early event leading to epigenetic silencing of target genes in murine and human CLL. These results provide strong rationale for the development of strategies to target NF-\u03baB components in CLL and potentially other B-cell malignancies.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0906455106","type":"journal-article","created":{"date-parts":[[2009,7,28]],"date-time":"2009-07-28T22:43:04Z","timestamp":1248820984000},"page":"13433-13438","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":77,"title":["Epigenetic changes during disease progression in a murine model of human chronic lymphocytic leukemia"],"prefix":"10.1073","volume":"106","author":[{"given":"Shih-Shih","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, the Comprehensive Cancer Center,"},{"name":"Department of Molecular Genetics,"},{"name":"Division of Hematology-Oncology, Department of Medicine, Ohio State University, Columbus, OH 43210;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aparna","family":"Raval","sequence":"additional","affiliation":[{"name":"Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, the Comprehensive Cancer Center,"},{"name":"Department of Oncology, CCSR 2250, Stanford University, Stanford, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy J.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Division of Hematology-Oncology, Department of Medicine, Ohio State University, Columbus, OH 43210;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin","family":"Hertlein","sequence":"additional","affiliation":[{"name":"Division of Hematology-Oncology, Department of Medicine, Ohio State University, Columbus, OH 43210;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Te-Hui","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, the Comprehensive Cancer Center,"},{"name":"Department of Infectious Disease, The Children's Hospital of Philadelphia, Philadelphia, PA 19104;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor X.","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, the Comprehensive Cancer Center,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mara H.","family":"Sherman","sequence":"additional","affiliation":[{"name":"Molecular Biology Institute, Department of Pathology and Laboratory Medicine, Broad Stem Cell Research Center, and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Jun","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Hematology-Oncology, Department of Medicine, Ohio State University, Columbus, OH 43210;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David W.","family":"Dawson","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease, The Children's Hospital of Philadelphia, Philadelphia, PA 19104;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie E.","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Lanasa","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, NC 27710; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandya","family":"Liyanarachchi","sequence":"additional","affiliation":[{"name":"Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, the Comprehensive Cancer Center,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas S.","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido","family":"Marcucci","sequence":"additional","affiliation":[{"name":"Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, the Comprehensive Cancer Center,"},{"name":"Department of Molecular Genetics,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuri","family":"Pekarsky","sequence":"additional","affiliation":[{"name":"Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, the Comprehensive Cancer Center,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramana","family":"Davuluri","sequence":"additional","affiliation":[{"name":"Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, the Comprehensive Cancer Center,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo M.","family":"Croce","sequence":"additional","affiliation":[{"name":"Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, the Comprehensive Cancer Center,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis C.","family":"Guttridge","sequence":"additional","affiliation":[{"name":"Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, the Comprehensive Cancer Center,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Teitell","sequence":"additional","affiliation":[{"name":"Molecular Biology Institute, Department of Pathology and Laboratory Medicine, Broad Stem Cell Research Center, and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Byrd","sequence":"additional","affiliation":[{"name":"Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, the Comprehensive Cancer Center,"},{"name":"Division of Hematology-Oncology, Department of Medicine, Ohio State University, Columbus, OH 43210;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Plass","sequence":"additional","affiliation":[{"name":"Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, the Comprehensive Cancer Center,"},{"name":"Division of Epigenomics and Cancer Risk, German Cancer Research Center, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2009,8,11]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.01.029"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1598"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.10.036"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2008.11.009"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2270"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/72785"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1535-6108(02)00234-9"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1866"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1083558"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1799"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.102181599"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-12-011213"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2007.05.020"},{"key":"e_1_3_3_14_2","first-page":"53","article-title":"Restriction landmark genome scanning","volume":"200","author":"Costello JF","year":"2002","unstructured":"JF Costello, C Plass, WK Cavenee, Restriction landmark genome scanning. 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