{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T06:42:04Z","timestamp":1791096124943,"version":"4.1.0"},"reference-count":30,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"17","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCO"],"published-print":{"date-parts":[[2005,6,10]]},"abstract":"<jats:sec><jats:title>Purpose<\/jats:title><jats:p> Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease for which natural history can be predicted based on the presence or absence of immunoglobulin (Ig) variable heavy chain (V<jats:sub>H<\/jats:sub>) gene mutations. Herein we report selective epigenetic silencing of the transcription factor TWIST2 (DERMO1) in Ig V<jats:sub>H<\/jats:sub> mutated CLL and describe a semiquantitative assay to study promoter methylation of this gene in primary tumor cells. <\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and Methods<\/jats:title><jats:p> TWIST2 promoter methylation was identified by restriction landmark genome scanning. Southern blot (SB), bisulfite sequencing, and combined bisulfite restriction analysis (COBRA), and quantitative SB-COBRA was performed to study methylation of the TWIST2 promoter. Reverse transcription polymerase chain reaction assays were used to study TWIST2 expression in CLL cells. <\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p> Following identification and confirmation of TWIST2 methylation in CLL patients, we demonstrated that expression of this transcription factor is related to the degree of promoter methylation. Expression of TWIST2 in a CLL cell line in which the promoter is methylated was increased following decitabine treatment. We next studied 53 patients by COBRA and demonstrated that 72% of patient samples with mutated Ig V<jats:sub>H<\/jats:sub> show TWIST2 methylation, while only 16% of patient samples with unmutated Ig V<jats:sub>H<\/jats:sub> were methylated (P &lt; .001). In a subset of patients, methylation of TWIST2 correlated with mRNA expression. <\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p> TWIST2 is differentially methylated in CLL cells relative to Ig V<jats:sub>H<\/jats:sub> mutational status and can be quantitatively monitored by SB-COBRA. Based on the known role of TWIST2 in silencing p53 function in other malignancies, future studies should focus on the role of TWIST2 in CLL and related lymphoproliferative diseases. <\/jats:p><\/jats:sec>","DOI":"10.1200\/jco.2005.02.196","type":"journal-article","created":{"date-parts":[[2005,4,5]],"date-time":"2005-04-05T00:31:05Z","timestamp":1112661065000},"page":"3877-3885","source":"Crossref","is-referenced-by-count":83,"title":["<i>TWIST2<\/i> Demonstrates Differential Methylation in Immunoglobulin Variable Heavy Chain Mutated and Unmutated Chronic Lymphocytic Leukemia"],"prefix":"10.1200","volume":"23","author":[{"given":"Aparna","family":"Raval","sequence":"first","affiliation":[{"name":"From the Division of Human Cancer Genetics, Division of Hematology-Oncology, Department of Medicine, and Department of Biostatistics, The Ohio State University, Columbus, OH; and Division of Hematology\/Oncology, Department of Medicine, University of California, San Diego, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Lucas","sequence":"additional","affiliation":[{"name":"From the Division of Human Cancer Genetics, Division of Hematology-Oncology, Department of Medicine, and Department of Biostatistics, The Ohio State University, Columbus, OH; and Division of Hematology\/Oncology, Department of Medicine, University of California, San Diego, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer J.","family":"Matkovic","sequence":"additional","affiliation":[{"name":"From the Division of Human Cancer Genetics, Division of Hematology-Oncology, Department of Medicine, and Department of Biostatistics, The Ohio State University, Columbus, OH; and Division of Hematology\/Oncology, Department of Medicine, University of California, San Diego, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristi L.","family":"Bennett","sequence":"additional","affiliation":[{"name":"From the Division of Human Cancer Genetics, Division of Hematology-Oncology, Department of Medicine, and Department of Biostatistics, The Ohio State University, Columbus, OH; and Division of Hematology\/Oncology, Department of Medicine, University of California, San Diego, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandya","family":"Liyanarachchi","sequence":"additional","affiliation":[{"name":"From the Division of Human Cancer Genetics, Division of Hematology-Oncology, Department of Medicine, and Department of Biostatistics, The Ohio State University, Columbus, OH; and Division of Hematology\/Oncology, Department of Medicine, University of California, San Diego, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donn C.","family":"Young","sequence":"additional","affiliation":[{"name":"From the Division of Human Cancer Genetics, Division of Hematology-Oncology, Department of Medicine, and Department of Biostatistics, The Ohio State University, Columbus, OH; and Division of Hematology\/Oncology, Department of Medicine, University of California, San Diego, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Rassenti","sequence":"additional","affiliation":[{"name":"From the Division of Human Cancer Genetics, Division of Hematology-Oncology, Department of Medicine, and Department of Biostatistics, The Ohio State University, Columbus, OH; and Division of Hematology\/Oncology, Department of Medicine, University of California, San Diego, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J.","family":"Kipps","sequence":"additional","affiliation":[{"name":"From the Division of Human Cancer Genetics, Division of Hematology-Oncology, Department of Medicine, and Department of Biostatistics, The Ohio State University, Columbus, OH; and Division of Hematology\/Oncology, Department of Medicine, University of California, San Diego, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Grever","sequence":"additional","affiliation":[{"name":"From the Division of Human Cancer Genetics, Division of Hematology-Oncology, Department of Medicine, and Department of Biostatistics, The Ohio State University, Columbus, OH; and Division of Hematology\/Oncology, Department of Medicine, University of California, San Diego, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Byrd","sequence":"additional","affiliation":[{"name":"From the Division of Human Cancer Genetics, Division of Hematology-Oncology, Department of Medicine, and Department of Biostatistics, The Ohio State University, Columbus, OH; and Division of Hematology\/Oncology, Department of Medicine, University of California, San Diego, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Plass","sequence":"additional","affiliation":[{"name":"From the Division of Human Cancer Genetics, Division of Hematology-Oncology, Department of Medicine, and Department of Biostatistics, The Ohio State University, Columbus, OH; and Division of Hematology\/Oncology, Department of Medicine, University of California, San Diego, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"233","reference":[{"key":"BIB1","doi-asserted-by":"publisher","DOI":"10.3322\/canjclin.52.1.23"},{"key":"BIB2","doi-asserted-by":"publisher","DOI":"10.1097\/00001622-200001000-00004"},{"key":"BIB3","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V85.6.1580.bloodjournal8561580"},{"key":"BIB4","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(98)10117-4"},{"key":"BIB5","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003-04-1289"},{"key":"BIB6","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V94.6.1840"},{"key":"BIB7","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2141.2001.03149.x"},{"key":"BIB8","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V94.6.1848"},{"key":"BIB9","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2402537"},{"key":"BIB10","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa040857"},{"key":"BIB11","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V94.7.2445.419k19_2445_2451"},{"key":"BIB12","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V95.10.3208"},{"key":"BIB13","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/29.22.4598"},{"key":"BIB14","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1205600"},{"key":"BIB15","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.38.5.285"},{"key":"BIB16","doi-asserted-by":"publisher","DOI":"10.1038\/72785"},{"key":"BIB17","doi-asserted-by":"publisher","DOI":"10.1016\/S0003-2697(02)00033-7"},{"key":"BIB18","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-03-2870"},{"key":"BIB19","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110228200"},{"key":"BIB20","doi-asserted-by":"publisher","DOI":"10.1101\/gad.13.17.2207"},{"key":"BIB21","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V87.12.4990.bloodjournal87124990"},{"key":"BIB22","unstructured":"Wendel-Hansen V, Sallstrom J, De Campos-Lima PO, et al: Epstein-Barr virus (EBV) can immortalize B-cll cells activated by cytokines. 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