Methylation of the p15(INK4b) gene in myelodysplastic syndromes is frequent and acquired during disease progression
p15(INK4b) gene is an inhibitor of cyclin-dependent kinase (CDK) 4 and CDK6 whose expression is induced by transforming growth factor (TGF)beta. Recent reports suggest frequent methylation of the p15(INK4b) gene promoter in leukemias, and it has been proposed that this methylation could be necessary...
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| Veröffentlicht in: | Blood 1998-04, Vol.91 (8), p.2985-2990 |
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| creator | Quesnel, B Guillerm, G Vereecque, R Wattel, E Preudhomme, C Bauters, F Vanrumbeke, M Fenaux, P |
| description | p15(INK4b) gene is an inhibitor of cyclin-dependent kinase (CDK) 4 and CDK6 whose expression is induced by transforming growth factor (TGF)beta. Recent reports suggest frequent methylation of the p15(INK4b) gene promoter in leukemias, and it has been proposed that this methylation could be necessary for leukemic cells to escape TGF beta regulation. We investigated the methylation status of p15(INK4b) gene in 53 myelodysplastic syndromes (MDS) cases, including nine that had progressed to acute myeloid leukemia (AML), using a recently described sensitive method where polymerase chain reaction (PCR) is preceded by bisulfite modification of DNA (methylation specific PCR). p15(INK4b) methylation was observed in 20 of 53 (38%) of the cases. Twenty of the 24 patients with greater than 10% bone marrow blasts had p15(INK4b) methylation (including all nine patients who had progressed to AML) as compared with none of MDS patients with |
| doi_str_mv | 10.1182/blood.V91.8.2985.2985_2985_2990 |
| format | Article |
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Recent reports suggest frequent methylation of the p15(INK4b) gene promoter in leukemias, and it has been proposed that this methylation could be necessary for leukemic cells to escape TGF beta regulation. We investigated the methylation status of p15(INK4b) gene in 53 myelodysplastic syndromes (MDS) cases, including nine that had progressed to acute myeloid leukemia (AML), using a recently described sensitive method where polymerase chain reaction (PCR) is preceded by bisulfite modification of DNA (methylation specific PCR). p15(INK4b) methylation was observed in 20 of 53 (38%) of the cases. Twenty of the 24 patients with greater than 10% bone marrow blasts had p15(INK4b) methylation (including all nine patients who had progressed to AML) as compared with none of MDS patients with <10% bone marrow blasts. No correlation between karyotypic abnormalities and methylation status was found. Patients with p15(INK4b) methylation had a worse prognosis, but the prognostic significance of p15(INK4b) methylation was no more found by multivariate analysis, due to its strong correlation to the percentage of marrow blasts. In 10 MDS cases, sequential DNA samples were available. In five of them, methylation of the p15(INK4b) gene was detected at leukemic transformation, but not at diagnosis. Our results showed that methylation of the p15(INK4b) gene in MDS is correlated with blastic bone marrow involvement and increases with disease evolution toward AML. It suggests that proliferation of leukemic cells might require an escape of regulation of the G1 phase of the cell cycle, and possibly of TGF beta inhibitory effect.</description><identifier>ISSN: 0006-4971</identifier><identifier>DOI: 10.1182/blood.V91.8.2985.2985_2985_2990</identifier><identifier>PMID: 9531610</identifier><language>eng</language><publisher>United States</publisher><subject>Carrier Proteins - genetics ; Cell Cycle Proteins ; Cyclin-Dependent Kinase Inhibitor p15 ; Cyclin-Dependent Kinase Inhibitor p16 ; DNA Methylation ; Genes, Tumor Suppressor ; Humans ; Myelodysplastic Syndromes - genetics ; Myelodysplastic Syndromes - mortality ; Myelodysplastic Syndromes - pathology ; Prognosis ; Survival Analysis ; Tumor Suppressor Proteins</subject><ispartof>Blood, 1998-04, Vol.91 (8), p.2985-2990</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c268t-3e7de69b197f8ddda757c0a99dc0d71e691f08e13e0105f811e632fe149d73b63</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,27928,27929</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9531610$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Quesnel, B</creatorcontrib><creatorcontrib>Guillerm, G</creatorcontrib><creatorcontrib>Vereecque, R</creatorcontrib><creatorcontrib>Wattel, E</creatorcontrib><creatorcontrib>Preudhomme, C</creatorcontrib><creatorcontrib>Bauters, F</creatorcontrib><creatorcontrib>Vanrumbeke, M</creatorcontrib><creatorcontrib>Fenaux, P</creatorcontrib><title>Methylation of the p15(INK4b) gene in myelodysplastic syndromes is frequent and acquired during disease progression</title><title>Blood</title><addtitle>Blood</addtitle><description>p15(INK4b) gene is an inhibitor of cyclin-dependent kinase (CDK) 4 and CDK6 whose expression is induced by transforming growth factor (TGF)beta. Recent reports suggest frequent methylation of the p15(INK4b) gene promoter in leukemias, and it has been proposed that this methylation could be necessary for leukemic cells to escape TGF beta regulation. We investigated the methylation status of p15(INK4b) gene in 53 myelodysplastic syndromes (MDS) cases, including nine that had progressed to acute myeloid leukemia (AML), using a recently described sensitive method where polymerase chain reaction (PCR) is preceded by bisulfite modification of DNA (methylation specific PCR). p15(INK4b) methylation was observed in 20 of 53 (38%) of the cases. Twenty of the 24 patients with greater than 10% bone marrow blasts had p15(INK4b) methylation (including all nine patients who had progressed to AML) as compared with none of MDS patients with <10% bone marrow blasts. No correlation between karyotypic abnormalities and methylation status was found. Patients with p15(INK4b) methylation had a worse prognosis, but the prognostic significance of p15(INK4b) methylation was no more found by multivariate analysis, due to its strong correlation to the percentage of marrow blasts. In 10 MDS cases, sequential DNA samples were available. In five of them, methylation of the p15(INK4b) gene was detected at leukemic transformation, but not at diagnosis. Our results showed that methylation of the p15(INK4b) gene in MDS is correlated with blastic bone marrow involvement and increases with disease evolution toward AML. It suggests that proliferation of leukemic cells might require an escape of regulation of the G1 phase of the cell cycle, and possibly of TGF beta inhibitory effect.</description><subject>Carrier Proteins - genetics</subject><subject>Cell Cycle Proteins</subject><subject>Cyclin-Dependent Kinase Inhibitor p15</subject><subject>Cyclin-Dependent Kinase Inhibitor p16</subject><subject>DNA Methylation</subject><subject>Genes, Tumor Suppressor</subject><subject>Humans</subject><subject>Myelodysplastic Syndromes - genetics</subject><subject>Myelodysplastic Syndromes - mortality</subject><subject>Myelodysplastic Syndromes - pathology</subject><subject>Prognosis</subject><subject>Survival Analysis</subject><subject>Tumor Suppressor Proteins</subject><issn>0006-4971</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNotUMtOwzAQ9AFUSuETkHzicUjwxklsH1HFo6LABbhGTrxpjRKntZND_p4IcpmVZkczoyHkBlgMIJP7suk6E38riGWcKJn9QTGDYidkyRjLo1QJOCPnIfwwBilPsgVZqIxDDmxJwhv2-7HRve0c7Wra75EeILvdvL-m5R3doUNqHW1HbDozhkOjQ28rGkZnfNdioDbQ2uNxQNdT7QzV1XGwHg01g7duR40NqMNk6rudxxCmnAtyWusm4OV8V-Tr6fFz_RJtP54364dtVCW57COOwmCuSlCilsYYLTJRMa2UqZgRML2gZhKBIwOW1RImiic1QqqM4GXOV-T633fKngqGvmhtqLBptMNuCIVQQgJXbBJezcKhbNEUB29b7cdiXon_At3_bX0</recordid><startdate>19980415</startdate><enddate>19980415</enddate><creator>Quesnel, B</creator><creator>Guillerm, G</creator><creator>Vereecque, R</creator><creator>Wattel, E</creator><creator>Preudhomme, C</creator><creator>Bauters, F</creator><creator>Vanrumbeke, M</creator><creator>Fenaux, P</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>19980415</creationdate><title>Methylation of the p15(INK4b) gene in myelodysplastic syndromes is frequent and acquired during disease progression</title><author>Quesnel, B ; Guillerm, G ; Vereecque, R ; Wattel, E ; Preudhomme, C ; Bauters, F ; Vanrumbeke, M ; Fenaux, P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c268t-3e7de69b197f8ddda757c0a99dc0d71e691f08e13e0105f811e632fe149d73b63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>Carrier Proteins - genetics</topic><topic>Cell Cycle Proteins</topic><topic>Cyclin-Dependent Kinase Inhibitor p15</topic><topic>Cyclin-Dependent Kinase Inhibitor p16</topic><topic>DNA Methylation</topic><topic>Genes, Tumor Suppressor</topic><topic>Humans</topic><topic>Myelodysplastic Syndromes - genetics</topic><topic>Myelodysplastic Syndromes - mortality</topic><topic>Myelodysplastic Syndromes - pathology</topic><topic>Prognosis</topic><topic>Survival Analysis</topic><topic>Tumor Suppressor Proteins</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Quesnel, B</creatorcontrib><creatorcontrib>Guillerm, G</creatorcontrib><creatorcontrib>Vereecque, R</creatorcontrib><creatorcontrib>Wattel, E</creatorcontrib><creatorcontrib>Preudhomme, C</creatorcontrib><creatorcontrib>Bauters, F</creatorcontrib><creatorcontrib>Vanrumbeke, M</creatorcontrib><creatorcontrib>Fenaux, P</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Blood</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Quesnel, B</au><au>Guillerm, G</au><au>Vereecque, R</au><au>Wattel, E</au><au>Preudhomme, C</au><au>Bauters, F</au><au>Vanrumbeke, M</au><au>Fenaux, P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Methylation of the p15(INK4b) gene in myelodysplastic syndromes is frequent and acquired during disease progression</atitle><jtitle>Blood</jtitle><addtitle>Blood</addtitle><date>1998-04-15</date><risdate>1998</risdate><volume>91</volume><issue>8</issue><spage>2985</spage><epage>2990</epage><pages>2985-2990</pages><issn>0006-4971</issn><abstract>p15(INK4b) gene is an inhibitor of cyclin-dependent kinase (CDK) 4 and CDK6 whose expression is induced by transforming growth factor (TGF)beta. Recent reports suggest frequent methylation of the p15(INK4b) gene promoter in leukemias, and it has been proposed that this methylation could be necessary for leukemic cells to escape TGF beta regulation. We investigated the methylation status of p15(INK4b) gene in 53 myelodysplastic syndromes (MDS) cases, including nine that had progressed to acute myeloid leukemia (AML), using a recently described sensitive method where polymerase chain reaction (PCR) is preceded by bisulfite modification of DNA (methylation specific PCR). p15(INK4b) methylation was observed in 20 of 53 (38%) of the cases. Twenty of the 24 patients with greater than 10% bone marrow blasts had p15(INK4b) methylation (including all nine patients who had progressed to AML) as compared with none of MDS patients with <10% bone marrow blasts. No correlation between karyotypic abnormalities and methylation status was found. Patients with p15(INK4b) methylation had a worse prognosis, but the prognostic significance of p15(INK4b) methylation was no more found by multivariate analysis, due to its strong correlation to the percentage of marrow blasts. In 10 MDS cases, sequential DNA samples were available. In five of them, methylation of the p15(INK4b) gene was detected at leukemic transformation, but not at diagnosis. Our results showed that methylation of the p15(INK4b) gene in MDS is correlated with blastic bone marrow involvement and increases with disease evolution toward AML. It suggests that proliferation of leukemic cells might require an escape of regulation of the G1 phase of the cell cycle, and possibly of TGF beta inhibitory effect.</abstract><cop>United States</cop><pmid>9531610</pmid><doi>10.1182/blood.V91.8.2985.2985_2985_2990</doi><tpages>6</tpages></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Carrier Proteins - genetics Cell Cycle Proteins Cyclin-Dependent Kinase Inhibitor p15 Cyclin-Dependent Kinase Inhibitor p16 DNA Methylation Genes, Tumor Suppressor Humans Myelodysplastic Syndromes - genetics Myelodysplastic Syndromes - mortality Myelodysplastic Syndromes - pathology Prognosis Survival Analysis Tumor Suppressor Proteins |
| title | Methylation of the p15(INK4b) gene in myelodysplastic syndromes is frequent and acquired during disease progression |
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