MLL-AF9 and MLL-AF4 oncofusion proteins bind a distinct enhancer repertoire and target the RUNX1 program in 11q23 acute myeloid leukemia
In 11q23 leukemias, the N-terminal part of the mixed lineage leukemia (MLL) gene is fused to >60 different partner genes. In order to define a core set of MLL rearranged targets, we investigated the genome-wide binding of the MLL-AF9 and MLL-AF4 fusion proteins and associated epigenetic signature...
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| Veröffentlicht in: | Oncogene 2017-06, Vol.36 (23), p.3346-3356 |
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| creator | Prange, K H M Mandoli, A Kuznetsova, T Wang, S-Y Sotoca, A M Marneth, A E van der Reijden, B A Stunnenberg, H G Martens, J H A |
| description | In 11q23 leukemias, the N-terminal part of the mixed lineage leukemia (MLL) gene is fused to >60 different partner genes. In order to define a core set of MLL rearranged targets, we investigated the genome-wide binding of the MLL-AF9 and MLL-AF4 fusion proteins and associated epigenetic signatures in acute myeloid leukemia (AML) cell lines THP-1 and MV4-11. We uncovered both common as well as specific MLL-AF9 and MLL-AF4 target genes, which were all marked by H3K79me2, H3K27ac and H3K4me3. Apart from promoter binding, we also identified MLL-AF9 and MLL-AF4 binding at specific subsets of non-overlapping active distal regulatory elements. Despite this differential enhancer binding, MLL-AF9 and MLL-AF4 still direct a common gene program, which represents part of the RUNX1 gene program and constitutes of CD34
+
and monocyte-specific genes. Comparing these data sets identified several zinc finger transcription factors (TFs) as potential MLL-AF9 co-regulators. Together, these results suggest that MLL fusions collaborate with specific subsets of TFs to deregulate the RUNX1 gene program in 11q23 AMLs. |
| doi_str_mv | 10.1038/onc.2016.488 |
| format | Article |
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+
and monocyte-specific genes. Comparing these data sets identified several zinc finger transcription factors (TFs) as potential MLL-AF9 co-regulators. Together, these results suggest that MLL fusions collaborate with specific subsets of TFs to deregulate the RUNX1 gene program in 11q23 AMLs.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/onc.2016.488</identifier><identifier>PMID: 28114278</identifier><identifier>CODEN: ONCNES</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/106 ; 45/47 ; 45/77 ; 631/208/69 ; 631/337/100/2285 ; 631/337/176 ; 631/337/572 ; 631/67/1990/283/1897 ; Acute myelocytic leukemia ; Adult ; Antibodies ; Apoptosis ; Binding sites ; Care and treatment ; Cell Biology ; Chromosomes, Human, Pair 11 - genetics ; Core Binding Factor Alpha 2 Subunit - genetics ; Core Binding Factor Alpha 2 Subunit - metabolism ; Development and progression ; Enhancer Elements, Genetic ; Epigenetics ; Female ; Gene expression ; Gene Expression Regulation, Neoplastic ; Genes ; Genetic aspects ; Genomes ; Health aspects ; High-Throughput Nucleotide Sequencing - methods ; Human Genetics ; Humans ; Infant ; Internal Medicine ; Kinases ; Leukemia ; Leukemia, Myeloid, Acute - genetics ; Leukemia, Myeloid, Acute - metabolism ; Leukemia, Myeloid, Acute - pathology ; Life sciences ; Male ; Medicine ; Medicine & Public Health ; Middle Aged ; Molecular biology ; Myeloid-Lymphoid Leukemia Protein - genetics ; Myeloid-Lymphoid Leukemia Protein - metabolism ; Neoplasm Staging ; Oncogene Proteins, Fusion - genetics ; Oncogene Proteins, Fusion - metabolism ; Oncogenes ; Oncology ; Original ; original-article ; Prognosis ; Promoter Regions, Genetic ; Proteins ; RNA polymerase ; Transcription factors</subject><ispartof>Oncogene, 2017-06, Vol.36 (23), p.3346-3356</ispartof><rights>The Author(s) 2017</rights><rights>COPYRIGHT 2017 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jun 8, 2017</rights><rights>Copyright © 2017 The Author(s) 2017 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c616t-4cb6d837ee0cc7562ce9e3f96e1596773081342d2f5734b527e119471f5a88803</citedby><cites>FETCH-LOGICAL-c616t-4cb6d837ee0cc7562ce9e3f96e1596773081342d2f5734b527e119471f5a88803</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/onc.2016.488$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/onc.2016.488$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,27903,27904,41467,42536,51297</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28114278$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Prange, K H M</creatorcontrib><creatorcontrib>Mandoli, A</creatorcontrib><creatorcontrib>Kuznetsova, T</creatorcontrib><creatorcontrib>Wang, S-Y</creatorcontrib><creatorcontrib>Sotoca, A M</creatorcontrib><creatorcontrib>Marneth, A E</creatorcontrib><creatorcontrib>van der Reijden, B A</creatorcontrib><creatorcontrib>Stunnenberg, H G</creatorcontrib><creatorcontrib>Martens, J H A</creatorcontrib><title>MLL-AF9 and MLL-AF4 oncofusion proteins bind a distinct enhancer repertoire and target the RUNX1 program in 11q23 acute myeloid leukemia</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>In 11q23 leukemias, the N-terminal part of the mixed lineage leukemia (MLL) gene is fused to >60 different partner genes. In order to define a core set of MLL rearranged targets, we investigated the genome-wide binding of the MLL-AF9 and MLL-AF4 fusion proteins and associated epigenetic signatures in acute myeloid leukemia (AML) cell lines THP-1 and MV4-11. We uncovered both common as well as specific MLL-AF9 and MLL-AF4 target genes, which were all marked by H3K79me2, H3K27ac and H3K4me3. Apart from promoter binding, we also identified MLL-AF9 and MLL-AF4 binding at specific subsets of non-overlapping active distal regulatory elements. Despite this differential enhancer binding, MLL-AF9 and MLL-AF4 still direct a common gene program, which represents part of the RUNX1 gene program and constitutes of CD34
+
and monocyte-specific genes. Comparing these data sets identified several zinc finger transcription factors (TFs) as potential MLL-AF9 co-regulators. Together, these results suggest that MLL fusions collaborate with specific subsets of TFs to deregulate the RUNX1 gene program in 11q23 AMLs.</description><subject>13/106</subject><subject>45/47</subject><subject>45/77</subject><subject>631/208/69</subject><subject>631/337/100/2285</subject><subject>631/337/176</subject><subject>631/337/572</subject><subject>631/67/1990/283/1897</subject><subject>Acute myelocytic leukemia</subject><subject>Adult</subject><subject>Antibodies</subject><subject>Apoptosis</subject><subject>Binding sites</subject><subject>Care and treatment</subject><subject>Cell Biology</subject><subject>Chromosomes, Human, Pair 11 - genetics</subject><subject>Core Binding Factor Alpha 2 Subunit - genetics</subject><subject>Core Binding Factor Alpha 2 Subunit - metabolism</subject><subject>Development and progression</subject><subject>Enhancer Elements, Genetic</subject><subject>Epigenetics</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genomes</subject><subject>Health aspects</subject><subject>High-Throughput Nucleotide Sequencing - methods</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Infant</subject><subject>Internal Medicine</subject><subject>Kinases</subject><subject>Leukemia</subject><subject>Leukemia, Myeloid, Acute - genetics</subject><subject>Leukemia, Myeloid, Acute - metabolism</subject><subject>Leukemia, Myeloid, Acute - pathology</subject><subject>Life sciences</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Middle Aged</subject><subject>Molecular biology</subject><subject>Myeloid-Lymphoid Leukemia Protein - genetics</subject><subject>Myeloid-Lymphoid Leukemia Protein - metabolism</subject><subject>Neoplasm Staging</subject><subject>Oncogene Proteins, Fusion - genetics</subject><subject>Oncogene Proteins, Fusion - metabolism</subject><subject>Oncogenes</subject><subject>Oncology</subject><subject>Original</subject><subject>original-article</subject><subject>Prognosis</subject><subject>Promoter Regions, Genetic</subject><subject>Proteins</subject><subject>RNA polymerase</subject><subject>Transcription factors</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqFkk9rFDEYhwdR7Lp68ywBLz04a5LJ34uwFFuFVUEseAvZzDu7qTPJNpkR-g382Ga7tbZSkBwSkidP3rz8quolwQuCG_U2BregmIgFU-pRNSNMippzzR5XM6w5rjVt6FH1LOcLjLHUmD6tjqgihFGpZtWvT6tVvTzVyIYWHdYMFWXspuxjQLsUR_Aho7UvgEWtz6MPbkQQtjY4SCjBDtIYfYJrx2jTBkY0bgF9Pf_8newNm2QH5AMi5JI2yLppBDRcQR99i3qYfsDg7fPqSWf7DC9u5nl1fvr-28mHevXl7OPJclU7QcRYM7cWrWokAHZOckEdaGg6LYBwLaRssCINoy3tuGzYmlMJhGgmScetUgo38-rdwbub1gO0DsKYbG92yQ82XZlovbl_EvzWbOJPw5lkXPAiOL4RpHg5QR7N4LODvrcB4pQN0YQIoqSg_0dV-RPhTSl7Xr3-B72IUwqlE0WIhWZYM_aX2tgejA9dLCW6vdQsmWZCa4n3zy4eoMpoS6NdDND5sn_vwpvDBZdizgm623YQbPYhMyURZh8yU0JW8Fd3W3gL_0lVAeoDkMtR2EC685mHhL8BBRDYyw</recordid><startdate>20170608</startdate><enddate>20170608</enddate><creator>Prange, K H M</creator><creator>Mandoli, A</creator><creator>Kuznetsova, T</creator><creator>Wang, S-Y</creator><creator>Sotoca, A M</creator><creator>Marneth, A E</creator><creator>van der Reijden, B A</creator><creator>Stunnenberg, H G</creator><creator>Martens, J H A</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20170608</creationdate><title>MLL-AF9 and MLL-AF4 oncofusion proteins bind a distinct enhancer repertoire and target the RUNX1 program in 11q23 acute myeloid leukemia</title><author>Prange, K H M ; Mandoli, A ; Kuznetsova, T ; Wang, S-Y ; Sotoca, A M ; Marneth, A E ; van der Reijden, B A ; Stunnenberg, H G ; Martens, J H A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c616t-4cb6d837ee0cc7562ce9e3f96e1596773081342d2f5734b527e119471f5a88803</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>13/106</topic><topic>45/47</topic><topic>45/77</topic><topic>631/208/69</topic><topic>631/337/100/2285</topic><topic>631/337/176</topic><topic>631/337/572</topic><topic>631/67/1990/283/1897</topic><topic>Acute myelocytic leukemia</topic><topic>Adult</topic><topic>Antibodies</topic><topic>Apoptosis</topic><topic>Binding sites</topic><topic>Care and treatment</topic><topic>Cell Biology</topic><topic>Chromosomes, Human, Pair 11 - genetics</topic><topic>Core Binding Factor Alpha 2 Subunit - genetics</topic><topic>Core Binding Factor Alpha 2 Subunit - metabolism</topic><topic>Development and progression</topic><topic>Enhancer Elements, Genetic</topic><topic>Epigenetics</topic><topic>Female</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Genes</topic><topic>Genetic aspects</topic><topic>Genomes</topic><topic>Health aspects</topic><topic>High-Throughput Nucleotide Sequencing - methods</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Infant</topic><topic>Internal Medicine</topic><topic>Kinases</topic><topic>Leukemia</topic><topic>Leukemia, Myeloid, Acute - genetics</topic><topic>Leukemia, Myeloid, Acute - metabolism</topic><topic>Leukemia, Myeloid, Acute - pathology</topic><topic>Life sciences</topic><topic>Male</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Middle Aged</topic><topic>Molecular biology</topic><topic>Myeloid-Lymphoid Leukemia Protein - genetics</topic><topic>Myeloid-Lymphoid Leukemia Protein - metabolism</topic><topic>Neoplasm Staging</topic><topic>Oncogene Proteins, Fusion - genetics</topic><topic>Oncogene Proteins, Fusion - metabolism</topic><topic>Oncogenes</topic><topic>Oncology</topic><topic>Original</topic><topic>original-article</topic><topic>Prognosis</topic><topic>Promoter Regions, Genetic</topic><topic>Proteins</topic><topic>RNA polymerase</topic><topic>Transcription factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Prange, K H M</creatorcontrib><creatorcontrib>Mandoli, A</creatorcontrib><creatorcontrib>Kuznetsova, T</creatorcontrib><creatorcontrib>Wang, S-Y</creatorcontrib><creatorcontrib>Sotoca, A M</creatorcontrib><creatorcontrib>Marneth, A E</creatorcontrib><creatorcontrib>van der Reijden, B A</creatorcontrib><creatorcontrib>Stunnenberg, H G</creatorcontrib><creatorcontrib>Martens, J H A</creatorcontrib><collection>Springer Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Prange, K H M</au><au>Mandoli, A</au><au>Kuznetsova, T</au><au>Wang, S-Y</au><au>Sotoca, A M</au><au>Marneth, A E</au><au>van der Reijden, B A</au><au>Stunnenberg, H G</au><au>Martens, J H A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>MLL-AF9 and MLL-AF4 oncofusion proteins bind a distinct enhancer repertoire and target the RUNX1 program in 11q23 acute myeloid leukemia</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2017-06-08</date><risdate>2017</risdate><volume>36</volume><issue>23</issue><spage>3346</spage><epage>3356</epage><pages>3346-3356</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><coden>ONCNES</coden><abstract>In 11q23 leukemias, the N-terminal part of the mixed lineage leukemia (MLL) gene is fused to >60 different partner genes. In order to define a core set of MLL rearranged targets, we investigated the genome-wide binding of the MLL-AF9 and MLL-AF4 fusion proteins and associated epigenetic signatures in acute myeloid leukemia (AML) cell lines THP-1 and MV4-11. We uncovered both common as well as specific MLL-AF9 and MLL-AF4 target genes, which were all marked by H3K79me2, H3K27ac and H3K4me3. Apart from promoter binding, we also identified MLL-AF9 and MLL-AF4 binding at specific subsets of non-overlapping active distal regulatory elements. Despite this differential enhancer binding, MLL-AF9 and MLL-AF4 still direct a common gene program, which represents part of the RUNX1 gene program and constitutes of CD34
+
and monocyte-specific genes. Comparing these data sets identified several zinc finger transcription factors (TFs) as potential MLL-AF9 co-regulators. Together, these results suggest that MLL fusions collaborate with specific subsets of TFs to deregulate the RUNX1 gene program in 11q23 AMLs.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>28114278</pmid><doi>10.1038/onc.2016.488</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 13/106 45/47 45/77 631/208/69 631/337/100/2285 631/337/176 631/337/572 631/67/1990/283/1897 Acute myelocytic leukemia Adult Antibodies Apoptosis Binding sites Care and treatment Cell Biology Chromosomes, Human, Pair 11 - genetics Core Binding Factor Alpha 2 Subunit - genetics Core Binding Factor Alpha 2 Subunit - metabolism Development and progression Enhancer Elements, Genetic Epigenetics Female Gene expression Gene Expression Regulation, Neoplastic Genes Genetic aspects Genomes Health aspects High-Throughput Nucleotide Sequencing - methods Human Genetics Humans Infant Internal Medicine Kinases Leukemia Leukemia, Myeloid, Acute - genetics Leukemia, Myeloid, Acute - metabolism Leukemia, Myeloid, Acute - pathology Life sciences Male Medicine Medicine & Public Health Middle Aged Molecular biology Myeloid-Lymphoid Leukemia Protein - genetics Myeloid-Lymphoid Leukemia Protein - metabolism Neoplasm Staging Oncogene Proteins, Fusion - genetics Oncogene Proteins, Fusion - metabolism Oncogenes Oncology Original original-article Prognosis Promoter Regions, Genetic Proteins RNA polymerase Transcription factors |
| title | MLL-AF9 and MLL-AF4 oncofusion proteins bind a distinct enhancer repertoire and target the RUNX1 program in 11q23 acute myeloid leukemia |
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