CBX8, a Polycomb Group Protein, Is Essential for MLL-AF9-Induced Leukemogenesis
Chromosomal translocations involving the mixed lineage leukemia ( MLL) gene lead to the development of acute leukemias. Constitutive HOX gene activation by MLL fusion proteins is required for MLL-mediated leukemogenesis; however, the underlying mechanisms remain elusive. Here, we show that chromobox...
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| Veröffentlicht in: | Cancer cell 2011-11, Vol.20 (5), p.563-575 |
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| creator | Tan, Jiaying Jones, Morgan Koseki, Haruhiko Nakayama, Manabu Muntean, Andrew G. Maillard, Ivan Hess, Jay L. |
| description | Chromosomal translocations involving the mixed lineage leukemia (
MLL) gene lead to the development of acute leukemias. Constitutive
HOX gene activation by MLL fusion proteins is required for MLL-mediated leukemogenesis; however, the underlying mechanisms remain elusive. Here, we show that chromobox homolog 8 (CBX8), a Polycomb Group protein that interacts with MLL-AF9 and TIP60, is required for MLL-AF9-induced transcriptional activation and leukemogenesis. Conversely, both CBX8 ablation and specific disruption of the CBX8 interaction by point mutations in MLL-AF9 abrogate
HOX gene upregulation and abolish MLL-AF9 leukemic transformation. Surprisingly, Cbx8-deficient mice are viable and display no apparent hematopoietic defects. Together, our findings demonstrate that CBX8 plays an essential role in MLL-AF9 transcriptional regulation and leukemogenesis.
► CBX8 is essential for both initiation and maintenance of MLL-AF9 transformation ► CBX8 is crucial for MLL-AF9-induced transcriptional activation ► Role of CBX8 in MLL-AF9 leukemogenesis is independent of PRC1 ► CBX8 regulation of TIP60 localization contributes to MLL-AF9 transformation |
| doi_str_mv | 10.1016/j.ccr.2011.09.008 |
| format | Article |
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MLL) gene lead to the development of acute leukemias. Constitutive
HOX gene activation by MLL fusion proteins is required for MLL-mediated leukemogenesis; however, the underlying mechanisms remain elusive. Here, we show that chromobox homolog 8 (CBX8), a Polycomb Group protein that interacts with MLL-AF9 and TIP60, is required for MLL-AF9-induced transcriptional activation and leukemogenesis. Conversely, both CBX8 ablation and specific disruption of the CBX8 interaction by point mutations in MLL-AF9 abrogate
HOX gene upregulation and abolish MLL-AF9 leukemic transformation. Surprisingly, Cbx8-deficient mice are viable and display no apparent hematopoietic defects. Together, our findings demonstrate that CBX8 plays an essential role in MLL-AF9 transcriptional regulation and leukemogenesis.
► CBX8 is essential for both initiation and maintenance of MLL-AF9 transformation ► CBX8 is crucial for MLL-AF9-induced transcriptional activation ► Role of CBX8 in MLL-AF9 leukemogenesis is independent of PRC1 ► CBX8 regulation of TIP60 localization contributes to MLL-AF9 transformation</description><identifier>ISSN: 1535-6108</identifier><identifier>EISSN: 1878-3686</identifier><identifier>DOI: 10.1016/j.ccr.2011.09.008</identifier><identifier>PMID: 22094252</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Amino Acid Sequence ; Animals ; Cell Proliferation ; Cell Survival - genetics ; Cell Transformation, Neoplastic - genetics ; Gene Expression Regulation, Neoplastic ; HEK293 Cells ; HeLa Cells ; Hematopoiesis - genetics ; Homeodomain Proteins - genetics ; Humans ; Leukemia - genetics ; Mice ; Mitochondrial Membrane Transport Proteins ; Molecular Sequence Data ; Myeloid-Lymphoid Leukemia Protein - genetics ; Myeloid-Lymphoid Leukemia Protein - physiology ; Oncogene Proteins, Fusion - genetics ; Oncogene Proteins, Fusion - physiology ; Point Mutation ; Polycomb Repressive Complex 1 ; Polycomb-Group Proteins ; Protein Interaction Mapping ; Repressor Proteins - genetics ; Repressor Proteins - metabolism ; Repressor Proteins - physiology ; Sequence Alignment ; Translocation, Genetic</subject><ispartof>Cancer cell, 2011-11, Vol.20 (5), p.563-575</ispartof><rights>2011 Elsevier Inc.</rights><rights>2011 Elsevier Inc. All rights reserved.</rights><rights>2011 Elsevier Inc. All rights reserved. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c549t-e0afa950ca7c3cfaa72a0aca4cb1fb6ba13236dcbdd2d444228a6ce14837b1f3</citedby><cites>FETCH-LOGICAL-c549t-e0afa950ca7c3cfaa72a0aca4cb1fb6ba13236dcbdd2d444228a6ce14837b1f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1535610811003552$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22094252$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tan, Jiaying</creatorcontrib><creatorcontrib>Jones, Morgan</creatorcontrib><creatorcontrib>Koseki, Haruhiko</creatorcontrib><creatorcontrib>Nakayama, Manabu</creatorcontrib><creatorcontrib>Muntean, Andrew G.</creatorcontrib><creatorcontrib>Maillard, Ivan</creatorcontrib><creatorcontrib>Hess, Jay L.</creatorcontrib><title>CBX8, a Polycomb Group Protein, Is Essential for MLL-AF9-Induced Leukemogenesis</title><title>Cancer cell</title><addtitle>Cancer Cell</addtitle><description>Chromosomal translocations involving the mixed lineage leukemia (
MLL) gene lead to the development of acute leukemias. Constitutive
HOX gene activation by MLL fusion proteins is required for MLL-mediated leukemogenesis; however, the underlying mechanisms remain elusive. Here, we show that chromobox homolog 8 (CBX8), a Polycomb Group protein that interacts with MLL-AF9 and TIP60, is required for MLL-AF9-induced transcriptional activation and leukemogenesis. Conversely, both CBX8 ablation and specific disruption of the CBX8 interaction by point mutations in MLL-AF9 abrogate
HOX gene upregulation and abolish MLL-AF9 leukemic transformation. Surprisingly, Cbx8-deficient mice are viable and display no apparent hematopoietic defects. Together, our findings demonstrate that CBX8 plays an essential role in MLL-AF9 transcriptional regulation and leukemogenesis.
► CBX8 is essential for both initiation and maintenance of MLL-AF9 transformation ► CBX8 is crucial for MLL-AF9-induced transcriptional activation ► Role of CBX8 in MLL-AF9 leukemogenesis is independent of PRC1 ► CBX8 regulation of TIP60 localization contributes to MLL-AF9 transformation</description><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Cell Proliferation</subject><subject>Cell Survival - genetics</subject><subject>Cell Transformation, Neoplastic - genetics</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>HEK293 Cells</subject><subject>HeLa Cells</subject><subject>Hematopoiesis - genetics</subject><subject>Homeodomain Proteins - genetics</subject><subject>Humans</subject><subject>Leukemia - genetics</subject><subject>Mice</subject><subject>Mitochondrial Membrane Transport Proteins</subject><subject>Molecular Sequence Data</subject><subject>Myeloid-Lymphoid Leukemia Protein - genetics</subject><subject>Myeloid-Lymphoid Leukemia Protein - physiology</subject><subject>Oncogene Proteins, Fusion - genetics</subject><subject>Oncogene Proteins, Fusion - physiology</subject><subject>Point Mutation</subject><subject>Polycomb Repressive Complex 1</subject><subject>Polycomb-Group Proteins</subject><subject>Protein Interaction Mapping</subject><subject>Repressor Proteins - genetics</subject><subject>Repressor Proteins - metabolism</subject><subject>Repressor Proteins - physiology</subject><subject>Sequence Alignment</subject><subject>Translocation, Genetic</subject><issn>1535-6108</issn><issn>1878-3686</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU9v1DAQxS0EoqXwAbggHzk0wWPnjyMkpHbVlpWC2kMP3KyJMyleknixk0r99rjaUsGFky35955n3mPsPYgcBFSfdrm1IZcCIBdNLoR-wY5B1zpTla5epnupyqwCoY_Ymxh3Immgbl6zIylFU8hSHrPrzfl3fcqR3_jxwfqp41fBr3t-E_xCbj7l28gvYqR5cTjywQf-rW2zs8sm2879aqnnLa0_afJ3NFN08S17NeAY6d3TecJuLy9uN1-z9vpquzlrM1sWzZKRwAGbUlisrbIDYi1RoMXCdjB0VYegpKp62_W97IuikFJjZQkKrepEqBP25WC7X7uJepvmCziafXAThgfj0Zl_X2b3w9z5e6PS6lqrZPDxySD4XyvFxUwuWhpHnMmv0UBdggRZ15BQOKA2-BgDDc_fgDCPPZidST2Yxx6MaEzqIWk-_D3fs-JP8An4fAAohXTvKJhoHc0pUBfILqb37j_2vwHfIJkI</recordid><startdate>20111115</startdate><enddate>20111115</enddate><creator>Tan, Jiaying</creator><creator>Jones, Morgan</creator><creator>Koseki, Haruhiko</creator><creator>Nakayama, Manabu</creator><creator>Muntean, Andrew G.</creator><creator>Maillard, Ivan</creator><creator>Hess, Jay L.</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</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>7TO</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20111115</creationdate><title>CBX8, a Polycomb Group Protein, Is Essential for MLL-AF9-Induced Leukemogenesis</title><author>Tan, Jiaying ; Jones, Morgan ; Koseki, Haruhiko ; Nakayama, Manabu ; Muntean, Andrew G. ; Maillard, Ivan ; Hess, Jay L.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c549t-e0afa950ca7c3cfaa72a0aca4cb1fb6ba13236dcbdd2d444228a6ce14837b1f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Cell Proliferation</topic><topic>Cell Survival - genetics</topic><topic>Cell Transformation, Neoplastic - genetics</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>HEK293 Cells</topic><topic>HeLa Cells</topic><topic>Hematopoiesis - genetics</topic><topic>Homeodomain Proteins - genetics</topic><topic>Humans</topic><topic>Leukemia - genetics</topic><topic>Mice</topic><topic>Mitochondrial Membrane Transport Proteins</topic><topic>Molecular Sequence Data</topic><topic>Myeloid-Lymphoid Leukemia Protein - genetics</topic><topic>Myeloid-Lymphoid Leukemia Protein - physiology</topic><topic>Oncogene Proteins, Fusion - genetics</topic><topic>Oncogene Proteins, Fusion - physiology</topic><topic>Point Mutation</topic><topic>Polycomb Repressive Complex 1</topic><topic>Polycomb-Group Proteins</topic><topic>Protein Interaction Mapping</topic><topic>Repressor Proteins - genetics</topic><topic>Repressor Proteins - metabolism</topic><topic>Repressor Proteins - physiology</topic><topic>Sequence Alignment</topic><topic>Translocation, Genetic</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tan, Jiaying</creatorcontrib><creatorcontrib>Jones, Morgan</creatorcontrib><creatorcontrib>Koseki, Haruhiko</creatorcontrib><creatorcontrib>Nakayama, Manabu</creatorcontrib><creatorcontrib>Muntean, Andrew G.</creatorcontrib><creatorcontrib>Maillard, Ivan</creatorcontrib><creatorcontrib>Hess, Jay L.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect: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>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tan, Jiaying</au><au>Jones, Morgan</au><au>Koseki, Haruhiko</au><au>Nakayama, Manabu</au><au>Muntean, Andrew G.</au><au>Maillard, Ivan</au><au>Hess, Jay L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CBX8, a Polycomb Group Protein, Is Essential for MLL-AF9-Induced Leukemogenesis</atitle><jtitle>Cancer cell</jtitle><addtitle>Cancer Cell</addtitle><date>2011-11-15</date><risdate>2011</risdate><volume>20</volume><issue>5</issue><spage>563</spage><epage>575</epage><pages>563-575</pages><issn>1535-6108</issn><eissn>1878-3686</eissn><abstract>Chromosomal translocations involving the mixed lineage leukemia (
MLL) gene lead to the development of acute leukemias. Constitutive
HOX gene activation by MLL fusion proteins is required for MLL-mediated leukemogenesis; however, the underlying mechanisms remain elusive. Here, we show that chromobox homolog 8 (CBX8), a Polycomb Group protein that interacts with MLL-AF9 and TIP60, is required for MLL-AF9-induced transcriptional activation and leukemogenesis. Conversely, both CBX8 ablation and specific disruption of the CBX8 interaction by point mutations in MLL-AF9 abrogate
HOX gene upregulation and abolish MLL-AF9 leukemic transformation. Surprisingly, Cbx8-deficient mice are viable and display no apparent hematopoietic defects. Together, our findings demonstrate that CBX8 plays an essential role in MLL-AF9 transcriptional regulation and leukemogenesis.
► CBX8 is essential for both initiation and maintenance of MLL-AF9 transformation ► CBX8 is crucial for MLL-AF9-induced transcriptional activation ► Role of CBX8 in MLL-AF9 leukemogenesis is independent of PRC1 ► CBX8 regulation of TIP60 localization contributes to MLL-AF9 transformation</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>22094252</pmid><doi>10.1016/j.ccr.2011.09.008</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Cell Press Free Archives; Elsevier ScienceDirect Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Amino Acid Sequence Animals Cell Proliferation Cell Survival - genetics Cell Transformation, Neoplastic - genetics Gene Expression Regulation, Neoplastic HEK293 Cells HeLa Cells Hematopoiesis - genetics Homeodomain Proteins - genetics Humans Leukemia - genetics Mice Mitochondrial Membrane Transport Proteins Molecular Sequence Data Myeloid-Lymphoid Leukemia Protein - genetics Myeloid-Lymphoid Leukemia Protein - physiology Oncogene Proteins, Fusion - genetics Oncogene Proteins, Fusion - physiology Point Mutation Polycomb Repressive Complex 1 Polycomb-Group Proteins Protein Interaction Mapping Repressor Proteins - genetics Repressor Proteins - metabolism Repressor Proteins - physiology Sequence Alignment Translocation, Genetic |
| title | CBX8, a Polycomb Group Protein, Is Essential for MLL-AF9-Induced Leukemogenesis |
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