Attenuation of AML1-ETO cellular dysregulation correlates with increased leukemogenic potential
AML1-ETO (RUNX1-ETO) fusion proteins are generated by the 8;21 translocation, commonly found in acute myeloid leukemia, which fuses the AML1 (RUNX1) and ETO (MTG8, RUNX1T1) genes. Previous studies have shown that AML1-ETO interferes with AML1 function but requires additional cooperating mutations to...
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| Veröffentlicht in: | Blood 2013-05, Vol.121 (18), p.3714-3717 |
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| creator | DeKelver, Russell C. Yan, Ming Ahn, Eun-Young Shia, Wei-Jong Speck, Nancy A. Zhang, Dong-Er |
| description | AML1-ETO (RUNX1-ETO) fusion proteins are generated by the 8;21 translocation, commonly found in acute myeloid leukemia, which fuses the AML1 (RUNX1) and ETO (MTG8, RUNX1T1) genes. Previous studies have shown that AML1-ETO interferes with AML1 function but requires additional cooperating mutations to induce leukemia development. In mouse models, AML1-ETO forms lacking the C-terminus have been shown to have greatly enhanced leukemogenic potential. Here, we investigate the role of 2 AML1-ETO C-terminal-interacting proteins, N-CoR, a transcriptional corepressor, and SON, a splicing/transcription factor required for cell cycle progression, in AML1-ETO-induced leukemia development. AML1-ETO-W692A loses N-CoR binding at NHR4, displays attenuated transcriptional repression ability and decreased cellular dysregulation, and promotes leukemia in vivo. These results support the importance of the degree of dysregulation by AML1-ETO in cellular transformation and demonstrate that AML1-ETO-W692A can be used as an effective experimental model for determining which factors compromise the leukemogenic potential of AML1-ETO.
•AML1-ETO-W692A loses interaction between NHR4 and N-CoR, decreases AML1-ETO cellular dysregulation, and promotes leukemia development in mice. |
| doi_str_mv | 10.1182/blood-2012-11-465641 |
| format | Article |
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•AML1-ETO-W692A loses interaction between NHR4 and N-CoR, decreases AML1-ETO cellular dysregulation, and promotes leukemia development in mice.</description><identifier>ISSN: 0006-4971</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood-2012-11-465641</identifier><identifier>PMID: 23426948</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Brief Report ; Cell Transformation, Neoplastic - genetics ; Cells, Cultured ; Core Binding Factor Alpha 2 Subunit - genetics ; Core Binding Factor Alpha 2 Subunit - metabolism ; Down-Regulation - genetics ; Gene Expression Regulation, Leukemic ; HEK293 Cells ; Humans ; K562 Cells ; Leukemia - genetics ; Leukemia - pathology ; Mice ; Mice, Inbred C57BL ; Myeloid Neoplasia ; Nuclear Receptor Co-Repressor 1 - metabolism ; Oncogene Proteins, Fusion - genetics ; Oncogene Proteins, Fusion - metabolism ; Protein Binding - genetics ; RUNX1 Translocation Partner 1 Protein</subject><ispartof>Blood, 2013-05, Vol.121 (18), p.3714-3717</ispartof><rights>2013 American Society of Hematology</rights><rights>2013 by The American Society of Hematology 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c463t-6d8b8235e6a714c9bf43655c4dee697978e9c61d22d100a211596bfaef5a00fa3</citedby><cites>FETCH-LOGICAL-c463t-6d8b8235e6a714c9bf43655c4dee697978e9c61d22d100a211596bfaef5a00fa3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23426948$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>DeKelver, Russell C.</creatorcontrib><creatorcontrib>Yan, Ming</creatorcontrib><creatorcontrib>Ahn, Eun-Young</creatorcontrib><creatorcontrib>Shia, Wei-Jong</creatorcontrib><creatorcontrib>Speck, Nancy A.</creatorcontrib><creatorcontrib>Zhang, Dong-Er</creatorcontrib><title>Attenuation of AML1-ETO cellular dysregulation correlates with increased leukemogenic potential</title><title>Blood</title><addtitle>Blood</addtitle><description>AML1-ETO (RUNX1-ETO) fusion proteins are generated by the 8;21 translocation, commonly found in acute myeloid leukemia, which fuses the AML1 (RUNX1) and ETO (MTG8, RUNX1T1) genes. Previous studies have shown that AML1-ETO interferes with AML1 function but requires additional cooperating mutations to induce leukemia development. In mouse models, AML1-ETO forms lacking the C-terminus have been shown to have greatly enhanced leukemogenic potential. Here, we investigate the role of 2 AML1-ETO C-terminal-interacting proteins, N-CoR, a transcriptional corepressor, and SON, a splicing/transcription factor required for cell cycle progression, in AML1-ETO-induced leukemia development. AML1-ETO-W692A loses N-CoR binding at NHR4, displays attenuated transcriptional repression ability and decreased cellular dysregulation, and promotes leukemia in vivo. These results support the importance of the degree of dysregulation by AML1-ETO in cellular transformation and demonstrate that AML1-ETO-W692A can be used as an effective experimental model for determining which factors compromise the leukemogenic potential of AML1-ETO.
•AML1-ETO-W692A loses interaction between NHR4 and N-CoR, decreases AML1-ETO cellular dysregulation, and promotes leukemia development in mice.</description><subject>Animals</subject><subject>Brief Report</subject><subject>Cell Transformation, Neoplastic - genetics</subject><subject>Cells, Cultured</subject><subject>Core Binding Factor Alpha 2 Subunit - genetics</subject><subject>Core Binding Factor Alpha 2 Subunit - metabolism</subject><subject>Down-Regulation - genetics</subject><subject>Gene Expression Regulation, Leukemic</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>K562 Cells</subject><subject>Leukemia - genetics</subject><subject>Leukemia - pathology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Myeloid Neoplasia</subject><subject>Nuclear Receptor Co-Repressor 1 - metabolism</subject><subject>Oncogene Proteins, Fusion - genetics</subject><subject>Oncogene Proteins, Fusion - metabolism</subject><subject>Protein Binding - genetics</subject><subject>RUNX1 Translocation Partner 1 Protein</subject><issn>0006-4971</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1OwzAQhS0EglK4AUK5gMHjOE6yQapQ-ZGKuilry7EnrSGNKyct4vaYFgpsWM2M7PfezEfIBbArgIJfV433lnIGnAJQITMp4IAMIOMFZYyzQzJgjEkqyhxOyGnXvTAGIuXZMTnhqeCyFMWAqFHfY7vWvfNt4utk9DQBOp5NE4NNs250SOx7F3Ae2-0X40PA2GOXvLl-kbjWBNQd2qTB9Ssu_RxbZ5KVj669080ZOap10-H5Vx2S57vx7PaBTqb3j7ejCTVCpj2VtqgKnmYodQ7ClFUtUpllRlhEWeZlXmBpJFjOLTCmOUBWyqrWWGeasVqnQ3Kz812tqyVaE9ODbtQquKUO78prp_6-tG6h5n6jUinSXBbRQOwMTPBdvLjea4GpT-BqC1x9Ao-z2gGPssvfuXvRN-GfxTBev3EYVGcctgatC2h6Zb37P-EDJdqVKg</recordid><startdate>20130502</startdate><enddate>20130502</enddate><creator>DeKelver, Russell C.</creator><creator>Yan, Ming</creator><creator>Ahn, Eun-Young</creator><creator>Shia, Wei-Jong</creator><creator>Speck, Nancy A.</creator><creator>Zhang, Dong-Er</creator><general>Elsevier Inc</general><general>American Society of Hematology</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>5PM</scope></search><sort><creationdate>20130502</creationdate><title>Attenuation of AML1-ETO cellular dysregulation correlates with increased leukemogenic potential</title><author>DeKelver, Russell C. ; Yan, Ming ; Ahn, Eun-Young ; Shia, Wei-Jong ; Speck, Nancy A. ; Zhang, Dong-Er</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c463t-6d8b8235e6a714c9bf43655c4dee697978e9c61d22d100a211596bfaef5a00fa3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Brief Report</topic><topic>Cell Transformation, Neoplastic - genetics</topic><topic>Cells, Cultured</topic><topic>Core Binding Factor Alpha 2 Subunit - genetics</topic><topic>Core Binding Factor Alpha 2 Subunit - metabolism</topic><topic>Down-Regulation - genetics</topic><topic>Gene Expression Regulation, Leukemic</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>K562 Cells</topic><topic>Leukemia - genetics</topic><topic>Leukemia - pathology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Myeloid Neoplasia</topic><topic>Nuclear Receptor Co-Repressor 1 - metabolism</topic><topic>Oncogene Proteins, Fusion - genetics</topic><topic>Oncogene Proteins, Fusion - metabolism</topic><topic>Protein Binding - genetics</topic><topic>RUNX1 Translocation Partner 1 Protein</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>DeKelver, Russell C.</creatorcontrib><creatorcontrib>Yan, Ming</creatorcontrib><creatorcontrib>Ahn, Eun-Young</creatorcontrib><creatorcontrib>Shia, Wei-Jong</creatorcontrib><creatorcontrib>Speck, Nancy A.</creatorcontrib><creatorcontrib>Zhang, Dong-Er</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>PubMed Central (Full Participant titles)</collection><jtitle>Blood</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>DeKelver, Russell C.</au><au>Yan, Ming</au><au>Ahn, Eun-Young</au><au>Shia, Wei-Jong</au><au>Speck, Nancy A.</au><au>Zhang, Dong-Er</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Attenuation of AML1-ETO cellular dysregulation correlates with increased leukemogenic potential</atitle><jtitle>Blood</jtitle><addtitle>Blood</addtitle><date>2013-05-02</date><risdate>2013</risdate><volume>121</volume><issue>18</issue><spage>3714</spage><epage>3717</epage><pages>3714-3717</pages><issn>0006-4971</issn><eissn>1528-0020</eissn><abstract>AML1-ETO (RUNX1-ETO) fusion proteins are generated by the 8;21 translocation, commonly found in acute myeloid leukemia, which fuses the AML1 (RUNX1) and ETO (MTG8, RUNX1T1) genes. Previous studies have shown that AML1-ETO interferes with AML1 function but requires additional cooperating mutations to induce leukemia development. In mouse models, AML1-ETO forms lacking the C-terminus have been shown to have greatly enhanced leukemogenic potential. Here, we investigate the role of 2 AML1-ETO C-terminal-interacting proteins, N-CoR, a transcriptional corepressor, and SON, a splicing/transcription factor required for cell cycle progression, in AML1-ETO-induced leukemia development. AML1-ETO-W692A loses N-CoR binding at NHR4, displays attenuated transcriptional repression ability and decreased cellular dysregulation, and promotes leukemia in vivo. These results support the importance of the degree of dysregulation by AML1-ETO in cellular transformation and demonstrate that AML1-ETO-W692A can be used as an effective experimental model for determining which factors compromise the leukemogenic potential of AML1-ETO.
•AML1-ETO-W692A loses interaction between NHR4 and N-CoR, decreases AML1-ETO cellular dysregulation, and promotes leukemia development in mice.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>23426948</pmid><doi>10.1182/blood-2012-11-465641</doi><tpages>4</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Animals Brief Report Cell Transformation, Neoplastic - genetics Cells, Cultured Core Binding Factor Alpha 2 Subunit - genetics Core Binding Factor Alpha 2 Subunit - metabolism Down-Regulation - genetics Gene Expression Regulation, Leukemic HEK293 Cells Humans K562 Cells Leukemia - genetics Leukemia - pathology Mice Mice, Inbred C57BL Myeloid Neoplasia Nuclear Receptor Co-Repressor 1 - metabolism Oncogene Proteins, Fusion - genetics Oncogene Proteins, Fusion - metabolism Protein Binding - genetics RUNX1 Translocation Partner 1 Protein |
| title | Attenuation of AML1-ETO cellular dysregulation correlates with increased leukemogenic potential |
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