{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T20:58:27Z","timestamp":1791061107730,"version":"4.1.0"},"reference-count":39,"publisher":"American Society of Hematology","issue":"11","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2002,6,1]]},"abstract":"<jats:p>Loss of genomic material from chromosomal band 13q14.3 is the most common genetic imbalance in B-cell chronic lymphocytic leukemia (B-CLL) and mantle cell lymphoma, pointing to the involvement of this region in a tumor suppressor mechanism. From the minimally deleted region, 3 candidate genes have been isolated, RFP2, BCMS, and BCMSUN. DNA sequence analyses have failed to detect small mutations in any of these genes, suggesting a different pathomechanism, most likely haploinsufficiency. We, therefore, tested B-CLL patients for epigenetic aberrations by measuring expression of genes from 13q14.3 and methylation of their promotor region.RB1, CLLD7, KPNA3, CLLD6, andRFP2 were down-regulated in B-CLL patients as compared with B cells of healthy donors, with RFP2 showing the most pronounced loss of expression. To test whether this loss of gene expression is associated with methylation of CpG islands in the respective promotor regions, we performed methylation-sensitive quantitative polymerase chain reaction analyses and bisulfite sequencing on DNA from B-CLL patients. No difference in the methylation patterns could be detected in any CpG island of the minimally deleted region. Down-regulation of genes within chromosomal band 13q14.3 in B-CLL is in line with the concept of haploinsufficiency, but this tumor-specific phenomenon is not associated with DNA methylation.<\/jats:p>","DOI":"10.1182\/blood.v99.11.4116","type":"journal-article","created":{"date-parts":[[2002,10,1]],"date-time":"2002-10-01T17:48:18Z","timestamp":1033494498000},"page":"4116-4121","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":82,"title":["Down-regulation of candidate tumor suppressor genes within chromosome band 13q14.3 is independent of the DNA methylation pattern in B-cell chronic lymphocytic leukemia"],"prefix":"10.1182","volume":"99","author":[{"given":"Daniel","family":"Mertens","sequence":"first","affiliation":[{"name":"From the Abteilung \u201cOrganisation komplexer Genome,\u201d Deutsches Krebsforschungszentrum, Heidelberg, Germany; and Innere Medizin III, University of Ulm, Ulm, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Wolf","sequence":"additional","affiliation":[{"name":"From the Abteilung \u201cOrganisation komplexer Genome,\u201d Deutsches Krebsforschungszentrum, Heidelberg, Germany; and Innere Medizin III, University of Ulm, Ulm, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Schroeter","sequence":"additional","affiliation":[{"name":"From the Abteilung \u201cOrganisation komplexer Genome,\u201d Deutsches Krebsforschungszentrum, Heidelberg, Germany; and Innere Medizin III, University of Ulm, Ulm, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Schaffner","sequence":"additional","affiliation":[{"name":"From the Abteilung \u201cOrganisation komplexer Genome,\u201d Deutsches Krebsforschungszentrum, Heidelberg, Germany; and Innere Medizin III, University of Ulm, Ulm, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hartmut","family":"Do\u0308hner","sequence":"additional","affiliation":[{"name":"From the Abteilung \u201cOrganisation komplexer Genome,\u201d Deutsches Krebsforschungszentrum, Heidelberg, Germany; and Innere Medizin III, University of Ulm, Ulm, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Stilgenbauer","sequence":"additional","affiliation":[{"name":"From the Abteilung \u201cOrganisation komplexer Genome,\u201d Deutsches Krebsforschungszentrum, Heidelberg, Germany; and Innere Medizin III, University of Ulm, Ulm, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Lichter","sequence":"additional","affiliation":[{"name":"From the Abteilung \u201cOrganisation komplexer Genome,\u201d Deutsches Krebsforschungszentrum, Heidelberg, Germany; and Innere Medizin III, University of Ulm, Ulm, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"key":"2020021218362255800_B1","first-page":"88","article-title":"Cytogenetics and molecular genetics of chronic lymphocytic leukaemia.","volume":"84","author":"Oscier","year":"1999","journal-title":"Haematologica."},{"key":"2020021218362255800_B2","doi-asserted-by":"crossref","first-page":"1910","DOI":"10.1056\/NEJM200012283432602","article-title":"Genomic aberrations and survival in chronic lymphocytic leukemia.","volume":"343","author":"Do\u0308hner","year":"2000","journal-title":"N Engl J Med."},{"key":"2020021218362255800_B3","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1002\/(SICI)1098-2264(200003)27:3<285::AID-GCC9>3.0.CO;2-M","article-title":"t(11;14)-positive mantle cell lymphomas exhibit complex karyotypes and share similarities with B-cell chronic lymphocytic leukemia.","volume":"27","author":"Bentz","year":"2000","journal-title":"Genes Chromosomes Cancer."},{"key":"2020021218362255800_B4","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1182\/blood.V91.4.1382","article-title":"Detailed molecular delineation of 13q14.3 loss in B-cell chronic lymphocytic leukemia.","volume":"91","author":"Corcoran","year":"1998","journal-title":"Blood."},{"key":"2020021218362255800_B5","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1038\/sj.onc.1201764","article-title":"Expressed sequences as candidates for a novel tumor suppressor gene at band 13q14 in B-cell chronic lymphocytic leukemia and mantle cell lymphoma.","volume":"16","author":"Stilgenbauer","year":"1998","journal-title":"Oncogene."},{"key":"2020021218362255800_B6","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1006\/geno.1995.1260","article-title":"A yeast artificial chromosome contig that spans the RB1\u2013D13S31 interval on human chromosome 13 and encompasses the frequently deleted region in B-cell chronic lymphocytic leukemia.","volume":"30","author":"Hawthorn","year":"1995","journal-title":"Genomics."},{"key":"2020021218362255800_B7","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1006\/geno.1997.4747","article-title":"Cloning and gene mapping of the chromosome 13q14 region deleted in chronic lymphocytic leukemia.","volume":"42","author":"Kalachikov","year":"1997","journal-title":"Genomics."},{"key":"2020021218362255800_B8","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1006\/geno.1997.5008","article-title":"Construction of a 780-kb PAC, BAC, and cosmid contig encompassing the minimal critical deletion involved in B cell chronic lymphocytic leukemia at 13q14.3.","volume":"46","author":"Bouyge-Moreau","year":"1997","journal-title":"Genomics."},{"key":"2020021218362255800_B9","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/S0014-5793(98)00357-3","article-title":"A cosmid and cDNA fine physical map of a human chromosome 13q14 region frequently lost in B-cell chronic lymphocytic leukemia and identification of a new putative tumor suppressor gene, Leu5.","volume":"426","author":"Kapanadze","year":"1998","journal-title":"FEBS Lett."},{"key":"2020021218362255800_B10","doi-asserted-by":"crossref","first-page":"2463","DOI":"10.1038\/sj.onc.1201643","article-title":"Cloning of two candidate tumor suppressor genes within a 10 kb region on chromosome 13q14, frequently deleted in chronic lymphocytic leukemia.","volume":"15","author":"Liu","year":"1997","journal-title":"Oncogene."},{"key":"2020021218362255800_B11","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1006\/geno.1998.5464","article-title":"Assignment of 48 ESTs to chromosome 13 band q14.3 and expression pattern for ESTs located in the core region deleted in B-CLL.","volume":"52","author":"Bezieau","year":"1998","journal-title":"Genomics."},{"key":"2020021218362255800_B12","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1093\/hmg\/10.12.1275","article-title":"B-cell neoplasia associated gene with multiple splicing (BCMS): the candidate B-CLL gene on 13q14 comprises more than 560 kb covering all critical regions.","volume":"10","author":"Wolf","year":"2001","journal-title":"Hum Mol Genet."},{"key":"2020021218362255800_B13","doi-asserted-by":"crossref","first-page":"2098","DOI":"10.1182\/blood.V97.7.2098","article-title":"Nucleotide sequence, transcription map, and mutation analysis of the 13q14 chromosomal region deleted in B-cell chronic lymphocytic leukemia.","volume":"97","author":"Migliazza","year":"2001","journal-title":"Blood."},{"key":"2020021218362255800_B14","first-page":"722","article-title":"Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4B.","volume":"56","author":"Herman","year":"1996","journal-title":"Cancer Res."},{"key":"2020021218362255800_B15","first-page":"832","article-title":"Frequent and selective methylation of p15 and deletion of both p15 and p16 in T-cell acute lymphoblastic leukemia.","volume":"57","author":"Batova","year":"1997","journal-title":"Cancer Res."},{"key":"2020021218362255800_B16","doi-asserted-by":"crossref","first-page":"2445","DOI":"10.1182\/blood.V94.7.2445.419k19_2445_2451","article-title":"p15(INK4B) CpG island methylation in primary acute leukemia is heterogeneous and suggests density as a critical factor for transcriptional silencing.","volume":"94","author":"Cameron","year":"1999","journal-title":"Blood."},{"key":"2020021218362255800_B17","first-page":"880","article-title":"Allele-specific hypermethylation of the retinoblastoma tumor-suppressor gene.","volume":"48","author":"Sakai","year":"1991","journal-title":"Am J Hum Genet."},{"key":"2020021218362255800_B18","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1038\/5947","article-title":"Cancer epigenetics comes of age.","volume":"21","author":"Jones","year":"1999","journal-title":"Nat Genet."},{"key":"2020021218362255800_B19","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/S0168-9525(99)01971-X","article-title":"DNA hypermethylation in tumorigenesis: epigenetics joins genetics.","volume":"16","author":"Baylin","year":"2000","journal-title":"Trends Genet."},{"key":"2020021218362255800_B20","doi-asserted-by":"crossref","first-page":"2773","DOI":"10.1073\/pnas.050400997","article-title":"Mantle cell lymphoma is characterized by inactivation of the ATM gene.","volume":"97","author":"Schaffner","year":"2000","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2020021218362255800_B21","doi-asserted-by":"crossref","first-page":"14863","DOI":"10.1073\/pnas.95.25.14863","article-title":"Cluster analysis and display of genome-wide expression patterns.","volume":"95","author":"Eisen","year":"1998","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2020021218362255800_B22","doi-asserted-by":"crossref","first-page":"2990","DOI":"10.1093\/nar\/22.15.2990","article-title":"High sensitivity mapping of methylated cytosines.","volume":"22","author":"Clark","year":"1994","journal-title":"Nucleic Acids Res."},{"key":"2020021218362255800_B23","doi-asserted-by":"crossref","first-page":"1820","DOI":"10.1182\/blood.V82.6.1820.1820","article-title":"bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia.","volume":"82","author":"Hanada","year":"1993","journal-title":"Blood."},{"key":"2020021218362255800_B24","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1126\/science.424726","article-title":"Methylation of mouse liver DNA studied by means of the restriction enzymes msp I and hpa II.","volume":"203","author":"Singer","year":"1979","journal-title":"Science."},{"key":"2020021218362255800_B25","doi-asserted-by":"crossref","first-page":"9821","DOI":"10.1073\/pnas.93.18.9821","article-title":"Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands.","volume":"93","author":"Herman","year":"1996","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2020021218362255800_B26","doi-asserted-by":"crossref","first-page":"E32","DOI":"10.1093\/nar\/28.8.e32","article-title":"MethyLight: a high-throughput assay to measure DNA methylation.","volume":"28","author":"Eads","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"2020021218362255800_B27","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1007\/s002770050373","article-title":"Molecular cytogenetic analysis of B-cell chronic lymphocytic leukemia.","volume":"76","author":"Stilgenbauer","year":"1998","journal-title":"Ann Hematol."},{"key":"2020021218362255800_B28","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1073\/pnas.68.4.820","article-title":"Mutation and cancer: statistical study of retinoblastoma.","volume":"68","author":"Knudson","year":"1971","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2020021218362255800_B29","first-page":"571","article-title":"Cloning and expression of the ret proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains.","volume":"3","author":"Takahashi","year":"1988","journal-title":"Oncogene."},{"key":"2020021218362255800_B30","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/S0092-8674(00)00077-5","article-title":"RING finger proteins: mediators of ubiquitin ligase activity.","volume":"102","author":"Joazeiro","year":"2000","journal-title":"Cell."},{"key":"2020021218362255800_B31","doi-asserted-by":"crossref","first-page":"39411","DOI":"10.1074\/jbc.M006585200","article-title":"RET finger protein is a transcriptional repressor and interacts with enhancer of polycomb that has dual transcriptional functions.","volume":"275","author":"Shimono","year":"2000","journal-title":"J Biol Chem."},{"key":"2020021218362255800_B32","doi-asserted-by":"crossref","first-page":"2074","DOI":"10.1182\/blood.V80.8.2074.bloodjournal8082074","article-title":"Genomic hypomethylation in human chronic lymphocytic leukemia.","volume":"80","author":"Wahlfors","year":"1992","journal-title":"Blood."},{"key":"2020021218362255800_B33","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1006\/geno.1998.5498","article-title":"cDNA cloning, gene characterization and 13q14.3 chromosomal assignment of CHC1-L, a chromosome condensation regulator-like guanine nucleotide exchange factor.","volume":"54","author":"Devilder","year":"1998","journal-title":"Genomics."},{"key":"2020021218362255800_B34","first-page":"2870","article-title":"Cloning and characterization of CLLD6, CLLD7, and CLLD8, novel candidate genes for leukemogenesis at chromosome 13q14, a region commonly deleted in B-cell chronic lymphocytic leukemia.","volume":"61","author":"Mabuchi","year":"2001","journal-title":"Cancer Res."},{"key":"2020021218362255800_B35","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1083\/jcb.139.2.313","article-title":"Nucleocytoplasmic recycling of the nuclear localization signal receptor alpha subunit in vivo is dependent on a nuclear export signal, energy, and RCC1.","volume":"139","author":"Boche","year":"1997","journal-title":"J Cell Biol."},{"key":"2020021218362255800_B36","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/0092-8674(92)90602-9","article-title":"Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias.","volume":"71","author":"Tkachuk","year":"1992","journal-title":"Cell."},{"key":"2020021218362255800_B37","first-page":"1778s","article-title":"Role of TCL1 and ALL1 in human leukemias and development.","volume":"59","author":"Croce","year":"1999","journal-title":"Cancer Res."},{"key":"2020021218362255800_B38","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1002\/(SICI)1098-2264(199907)25:3<222::AID-GCC4>3.0.CO;2-C","article-title":"Myeloid- and lymphoid-specific breakpoint cluster regions in chromosome band 13q14 in acute leukemia.","volume":"25","author":"Coignet","year":"1999","journal-title":"Genes Chromosomes Cancer."},{"key":"2020021218362255800_B39","first-page":"2409","article-title":"BMI-1 gene amplification and overexpression in hematological malignancies occur mainly in mantle cell lymphomas.","volume":"61","author":"Bea","year":"2001","journal-title":"Cancer Res."}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/99\/11\/4116\/1685649\/h81102004116.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/99\/11\/4116\/1685649\/h81102004116.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,2,12]],"date-time":"2020-02-12T19:37:03Z","timestamp":1581536223000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/99\/11\/4116\/106881\/Downregulation-of-candidate-tumor-suppressor-genes"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2002,6,1]]},"references-count":39,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2002,6,1]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.v99.11.4116","relation":{},"ISSN":["1528-0020","0006-4971"],"issn-type":[{"value":"1528-0020","type":"electronic"},{"value":"0006-4971","type":"print"}],"subject":[],"published":{"date-parts":[[2002,6,1]]}}}