MLL-Rearranged Leukemia Is Dependent on Aberrant H3K79 Methylation by DOT1L
The histone 3 lysine 79 (H3K79) methyltransferase Dot1l has been implicated in the development of leukemias bearing translocations of the Mixed Lineage Leukemia ( MLL) gene. We identified the MLL-fusion targets in an MLL-AF9 leukemia model, and conducted epigenetic profiling for H3K79me2, H3K4me3, H...
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| Veröffentlicht in: | Cancer cell 2011-07, Vol.20 (1), p.66-78 |
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| creator | Bernt, Kathrin M. Zhu, Nan Sinha, Amit U. Vempati, Sridhar Faber, Joerg Krivtsov, Andrei V. Feng, Zhaohui Punt, Natalie Daigle, Amanda Bullinger, Lars Pollock, Roy M. Richon, Victoria M. Kung, Andrew L. Armstrong, Scott A. |
| description | The histone 3 lysine 79 (H3K79) methyltransferase Dot1l has been implicated in the development of leukemias bearing translocations of the
Mixed Lineage Leukemia (
MLL) gene. We identified the MLL-fusion targets in an MLL-AF9 leukemia model, and conducted epigenetic profiling for H3K79me2, H3K4me3, H3K27me3, and H3K36me3 in hematopoietic progenitor and leukemia stem cells (LSCs). We found abnormal profiles only for H3K79me2 on MLL-AF9 fusion target loci in LSCs. Inactivation of Dot1l led to downregulation of direct MLL-AF9 targets and an
MLL translocation-associated gene expression signature, whereas global gene expression remained largely unaffected. Suppression of MLL translocation-associated gene expression corresponded with dependence of MLL-AF9 leukemia on Dot1l in vivo. These data point to DOT1L as a potential therapeutic target in
MLL-rearranged leukemia.
► MLL-AF9 promotes enhanced H3K79me2 at fusion target genes ► H3K79me2 is specifically abnormal as compared to other histone modifications ► Loss of Dot1l selectively decreases leukemia-associated gene expression ► Dot1l is absolutely required for MLL-rearranged leukemia cell growth in vitro and in vivo |
| doi_str_mv | 10.1016/j.ccr.2011.06.010 |
| format | Article |
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Mixed Lineage Leukemia (
MLL) gene. We identified the MLL-fusion targets in an MLL-AF9 leukemia model, and conducted epigenetic profiling for H3K79me2, H3K4me3, H3K27me3, and H3K36me3 in hematopoietic progenitor and leukemia stem cells (LSCs). We found abnormal profiles only for H3K79me2 on MLL-AF9 fusion target loci in LSCs. Inactivation of Dot1l led to downregulation of direct MLL-AF9 targets and an
MLL translocation-associated gene expression signature, whereas global gene expression remained largely unaffected. Suppression of MLL translocation-associated gene expression corresponded with dependence of MLL-AF9 leukemia on Dot1l in vivo. These data point to DOT1L as a potential therapeutic target in
MLL-rearranged leukemia.
► MLL-AF9 promotes enhanced H3K79me2 at fusion target genes ► H3K79me2 is specifically abnormal as compared to other histone modifications ► Loss of Dot1l selectively decreases leukemia-associated gene expression ► Dot1l is absolutely required for MLL-rearranged leukemia cell growth in vitro and in vivo</description><identifier>ISSN: 1535-6108</identifier><identifier>EISSN: 1878-3686</identifier><identifier>DOI: 10.1016/j.ccr.2011.06.010</identifier><identifier>PMID: 21741597</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Apoptosis ; Cell Cycle ; Cell Differentiation ; Cell Transformation, Neoplastic - metabolism ; Cell Transformation, Neoplastic - pathology ; Gene Rearrangement - genetics ; Genetic Loci - genetics ; Hematopoiesis ; Histones - metabolism ; Homeodomain Proteins - metabolism ; Humans ; Lysine - metabolism ; Methylation ; Methyltransferases - metabolism ; Mice ; Myeloid Ecotropic Viral Integration Site 1 Protein ; Myeloid Progenitor Cells - metabolism ; Myeloid Progenitor Cells - pathology ; Myeloid-Lymphoid Leukemia Protein - metabolism ; Neoplasm Proteins - metabolism ; Oncogene Proteins, Fusion - metabolism ; Protein Processing, Post-Translational</subject><ispartof>Cancer cell, 2011-07, Vol.20 (1), p.66-78</ispartof><rights>2011 Elsevier Inc.</rights><rights>Copyright © 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-c483t-843697013369e37c68de14cdb7e0376067791559a940e7afa7c6a524809957f73</citedby><cites>FETCH-LOGICAL-c483t-843697013369e37c68de14cdb7e0376067791559a940e7afa7c6a524809957f73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1535610811002285$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21741597$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bernt, Kathrin M.</creatorcontrib><creatorcontrib>Zhu, Nan</creatorcontrib><creatorcontrib>Sinha, Amit U.</creatorcontrib><creatorcontrib>Vempati, Sridhar</creatorcontrib><creatorcontrib>Faber, Joerg</creatorcontrib><creatorcontrib>Krivtsov, Andrei V.</creatorcontrib><creatorcontrib>Feng, Zhaohui</creatorcontrib><creatorcontrib>Punt, Natalie</creatorcontrib><creatorcontrib>Daigle, Amanda</creatorcontrib><creatorcontrib>Bullinger, Lars</creatorcontrib><creatorcontrib>Pollock, Roy M.</creatorcontrib><creatorcontrib>Richon, Victoria M.</creatorcontrib><creatorcontrib>Kung, Andrew L.</creatorcontrib><creatorcontrib>Armstrong, Scott A.</creatorcontrib><title>MLL-Rearranged Leukemia Is Dependent on Aberrant H3K79 Methylation by DOT1L</title><title>Cancer cell</title><addtitle>Cancer Cell</addtitle><description>The histone 3 lysine 79 (H3K79) methyltransferase Dot1l has been implicated in the development of leukemias bearing translocations of the
Mixed Lineage Leukemia (
MLL) gene. We identified the MLL-fusion targets in an MLL-AF9 leukemia model, and conducted epigenetic profiling for H3K79me2, H3K4me3, H3K27me3, and H3K36me3 in hematopoietic progenitor and leukemia stem cells (LSCs). We found abnormal profiles only for H3K79me2 on MLL-AF9 fusion target loci in LSCs. Inactivation of Dot1l led to downregulation of direct MLL-AF9 targets and an
MLL translocation-associated gene expression signature, whereas global gene expression remained largely unaffected. Suppression of MLL translocation-associated gene expression corresponded with dependence of MLL-AF9 leukemia on Dot1l in vivo. These data point to DOT1L as a potential therapeutic target in
MLL-rearranged leukemia.
► MLL-AF9 promotes enhanced H3K79me2 at fusion target genes ► H3K79me2 is specifically abnormal as compared to other histone modifications ► Loss of Dot1l selectively decreases leukemia-associated gene expression ► Dot1l is absolutely required for MLL-rearranged leukemia cell growth in vitro and in vivo</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Cell Cycle</subject><subject>Cell Differentiation</subject><subject>Cell Transformation, Neoplastic - metabolism</subject><subject>Cell Transformation, Neoplastic - pathology</subject><subject>Gene Rearrangement - genetics</subject><subject>Genetic Loci - genetics</subject><subject>Hematopoiesis</subject><subject>Histones - metabolism</subject><subject>Homeodomain Proteins - metabolism</subject><subject>Humans</subject><subject>Lysine - metabolism</subject><subject>Methylation</subject><subject>Methyltransferases - metabolism</subject><subject>Mice</subject><subject>Myeloid Ecotropic Viral Integration Site 1 Protein</subject><subject>Myeloid Progenitor Cells - metabolism</subject><subject>Myeloid Progenitor Cells - pathology</subject><subject>Myeloid-Lymphoid Leukemia Protein - metabolism</subject><subject>Neoplasm Proteins - metabolism</subject><subject>Oncogene Proteins, Fusion - metabolism</subject><subject>Protein Processing, Post-Translational</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>eNp9kU9r20AQxZfQErtpPkAuQcdepM5opf1DoWCStAlWCJTkvKxX42RdWXJ35YC_fdc4DcmlpxmY33szzGPsDKFAQPF1VTgXihIQCxAFIByxKSqpci6U-JD6mte5QFAT9inGFSQNSn3MJiXKCmstp2x-2zT5L7Ih2P6R2qyh7W9ae5vdxOySNtS31I_Z0GezBe2ZMbvmc6mzWxqfdp0dfRotdtnl3T02n9nHpe0inb7UE_bw4-r-4jpv7n7eXMya3FWKj7mquNASkKdCXDqhWsLKtQtJwKUAIaXGutZWV0DSLm1CbF1WCrSu5VLyE_b94LvZLtbUunRhsJ3ZBL-2YWcG6837Se-fzOPwbDgvtQKeDL68GIThz5biaNY-Ouo629OwjQYroXgpsYKE4gF1YYgx0PJ1DYLZh2BWJoVg9iEYECaFkDTnb-97Vfz7egK-HQBKX3r2FEx0nnpHrQ_kRtMO_j_2fwGZJZUD</recordid><startdate>20110712</startdate><enddate>20110712</enddate><creator>Bernt, Kathrin M.</creator><creator>Zhu, Nan</creator><creator>Sinha, Amit U.</creator><creator>Vempati, Sridhar</creator><creator>Faber, Joerg</creator><creator>Krivtsov, Andrei V.</creator><creator>Feng, Zhaohui</creator><creator>Punt, Natalie</creator><creator>Daigle, Amanda</creator><creator>Bullinger, Lars</creator><creator>Pollock, Roy M.</creator><creator>Richon, Victoria M.</creator><creator>Kung, Andrew L.</creator><creator>Armstrong, Scott A.</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>7TM</scope><scope>7TO</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20110712</creationdate><title>MLL-Rearranged Leukemia Is Dependent on Aberrant H3K79 Methylation by DOT1L</title><author>Bernt, Kathrin M. ; Zhu, Nan ; Sinha, Amit U. ; Vempati, Sridhar ; Faber, Joerg ; Krivtsov, Andrei V. ; Feng, Zhaohui ; Punt, Natalie ; Daigle, Amanda ; Bullinger, Lars ; Pollock, Roy M. ; Richon, Victoria M. ; Kung, Andrew L. ; Armstrong, Scott A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c483t-843697013369e37c68de14cdb7e0376067791559a940e7afa7c6a524809957f73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>Cell Cycle</topic><topic>Cell Differentiation</topic><topic>Cell Transformation, Neoplastic - metabolism</topic><topic>Cell Transformation, Neoplastic - pathology</topic><topic>Gene Rearrangement - genetics</topic><topic>Genetic Loci - genetics</topic><topic>Hematopoiesis</topic><topic>Histones - metabolism</topic><topic>Homeodomain Proteins - metabolism</topic><topic>Humans</topic><topic>Lysine - metabolism</topic><topic>Methylation</topic><topic>Methyltransferases - metabolism</topic><topic>Mice</topic><topic>Myeloid Ecotropic Viral Integration Site 1 Protein</topic><topic>Myeloid Progenitor Cells - metabolism</topic><topic>Myeloid Progenitor Cells - pathology</topic><topic>Myeloid-Lymphoid Leukemia Protein - metabolism</topic><topic>Neoplasm Proteins - metabolism</topic><topic>Oncogene Proteins, Fusion - metabolism</topic><topic>Protein Processing, Post-Translational</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bernt, Kathrin M.</creatorcontrib><creatorcontrib>Zhu, Nan</creatorcontrib><creatorcontrib>Sinha, Amit U.</creatorcontrib><creatorcontrib>Vempati, Sridhar</creatorcontrib><creatorcontrib>Faber, Joerg</creatorcontrib><creatorcontrib>Krivtsov, Andrei V.</creatorcontrib><creatorcontrib>Feng, Zhaohui</creatorcontrib><creatorcontrib>Punt, Natalie</creatorcontrib><creatorcontrib>Daigle, Amanda</creatorcontrib><creatorcontrib>Bullinger, Lars</creatorcontrib><creatorcontrib>Pollock, Roy M.</creatorcontrib><creatorcontrib>Richon, Victoria M.</creatorcontrib><creatorcontrib>Kung, Andrew L.</creatorcontrib><creatorcontrib>Armstrong, Scott A.</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>Nucleic Acids Abstracts</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>Bernt, Kathrin M.</au><au>Zhu, Nan</au><au>Sinha, Amit U.</au><au>Vempati, Sridhar</au><au>Faber, Joerg</au><au>Krivtsov, Andrei V.</au><au>Feng, Zhaohui</au><au>Punt, Natalie</au><au>Daigle, Amanda</au><au>Bullinger, Lars</au><au>Pollock, Roy M.</au><au>Richon, Victoria M.</au><au>Kung, Andrew L.</au><au>Armstrong, Scott A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>MLL-Rearranged Leukemia Is Dependent on Aberrant H3K79 Methylation by DOT1L</atitle><jtitle>Cancer cell</jtitle><addtitle>Cancer Cell</addtitle><date>2011-07-12</date><risdate>2011</risdate><volume>20</volume><issue>1</issue><spage>66</spage><epage>78</epage><pages>66-78</pages><issn>1535-6108</issn><eissn>1878-3686</eissn><abstract>The histone 3 lysine 79 (H3K79) methyltransferase Dot1l has been implicated in the development of leukemias bearing translocations of the
Mixed Lineage Leukemia (
MLL) gene. We identified the MLL-fusion targets in an MLL-AF9 leukemia model, and conducted epigenetic profiling for H3K79me2, H3K4me3, H3K27me3, and H3K36me3 in hematopoietic progenitor and leukemia stem cells (LSCs). We found abnormal profiles only for H3K79me2 on MLL-AF9 fusion target loci in LSCs. Inactivation of Dot1l led to downregulation of direct MLL-AF9 targets and an
MLL translocation-associated gene expression signature, whereas global gene expression remained largely unaffected. Suppression of MLL translocation-associated gene expression corresponded with dependence of MLL-AF9 leukemia on Dot1l in vivo. These data point to DOT1L as a potential therapeutic target in
MLL-rearranged leukemia.
► MLL-AF9 promotes enhanced H3K79me2 at fusion target genes ► H3K79me2 is specifically abnormal as compared to other histone modifications ► Loss of Dot1l selectively decreases leukemia-associated gene expression ► Dot1l is absolutely required for MLL-rearranged leukemia cell growth in vitro and in vivo</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>21741597</pmid><doi>10.1016/j.ccr.2011.06.010</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Apoptosis Cell Cycle Cell Differentiation Cell Transformation, Neoplastic - metabolism Cell Transformation, Neoplastic - pathology Gene Rearrangement - genetics Genetic Loci - genetics Hematopoiesis Histones - metabolism Homeodomain Proteins - metabolism Humans Lysine - metabolism Methylation Methyltransferases - metabolism Mice Myeloid Ecotropic Viral Integration Site 1 Protein Myeloid Progenitor Cells - metabolism Myeloid Progenitor Cells - pathology Myeloid-Lymphoid Leukemia Protein - metabolism Neoplasm Proteins - metabolism Oncogene Proteins, Fusion - metabolism Protein Processing, Post-Translational |
| title | MLL-Rearranged Leukemia Is Dependent on Aberrant H3K79 Methylation by DOT1L |
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