The methyltransferase G9a regulates HoxA9-dependent transcription in AML
Chromatin modulators are emerging as attractive drug targets, given their widespread implication in human cancers and susceptibility to pharmacological inhibition. Here we establish the histone methyltransferase G9a/EHMT2 as a selective regulator of fast proliferating myeloid progenitors with no dis...
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| Veröffentlicht in: | Genes & development 2014-02, Vol.28 (4), p.317-327 |
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| creator | Lehnertz, Bernhard Pabst, Caroline Su, Le Miller, Michelle Liu, Feng Yi, Lin Zhang, Regan Krosl, Jana Yung, Eric Kirschner, Jeanette Rosten, Patty Underhill, T Michael Jin, Jian Hébert, Josée Sauvageau, Guy Humphries, R Keith Rossi, Fabio M |
| description | Chromatin modulators are emerging as attractive drug targets, given their widespread implication in human cancers and susceptibility to pharmacological inhibition. Here we establish the histone methyltransferase G9a/EHMT2 as a selective regulator of fast proliferating myeloid progenitors with no discernible function in hematopoietic stem cells (HSCs). In mouse models of acute myeloid leukemia (AML), loss of G9a significantly delays disease progression and reduces leukemia stem cell (LSC) frequency. We connect this function of G9a to its methyltransferase activity and its interaction with the leukemogenic transcription factor HoxA9 and provide evidence that primary human AML cells are sensitive to G9A inhibition. Our results highlight a clinical potential of G9A inhibition as a means to counteract the proliferation and self-renewal of AML cells by attenuating HoxA9-dependent transcription. |
| doi_str_mv | 10.1101/gad.236794.113 |
| format | Article |
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Here we establish the histone methyltransferase G9a/EHMT2 as a selective regulator of fast proliferating myeloid progenitors with no discernible function in hematopoietic stem cells (HSCs). In mouse models of acute myeloid leukemia (AML), loss of G9a significantly delays disease progression and reduces leukemia stem cell (LSC) frequency. We connect this function of G9a to its methyltransferase activity and its interaction with the leukemogenic transcription factor HoxA9 and provide evidence that primary human AML cells are sensitive to G9A inhibition. Our results highlight a clinical potential of G9A inhibition as a means to counteract the proliferation and self-renewal of AML cells by attenuating HoxA9-dependent transcription.</description><identifier>ISSN: 0890-9369</identifier><identifier>EISSN: 1549-5477</identifier><identifier>DOI: 10.1101/gad.236794.113</identifier><identifier>PMID: 24532712</identifier><language>eng</language><publisher>United States: Cold Spring Harbor Laboratory Press</publisher><subject>Animals ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Cells, Cultured ; Enzyme Inhibitors - pharmacology ; Gene Expression Regulation, Neoplastic ; HEK293 Cells ; Hematopoietic Stem Cells - enzymology ; Histone-Lysine N-Methyltransferase - genetics ; Histone-Lysine N-Methyltransferase - metabolism ; Homeodomain Proteins - metabolism ; Humans ; Leukemia, Myeloid, Acute - enzymology ; Leukemia, Myeloid, Acute - genetics ; Leukemia, Myeloid, Acute - pathology ; Mice, Inbred C57BL ; Quinazolines - pharmacology ; Research Paper</subject><ispartof>Genes & development, 2014-02, Vol.28 (4), p.317-327</ispartof><rights>2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c489t-df61f0357a0162244d7174a15b3719293998a3656736e37b658191ff20247d153</citedby><cites>FETCH-LOGICAL-c489t-df61f0357a0162244d7174a15b3719293998a3656736e37b658191ff20247d153</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937511/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937511/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24532712$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lehnertz, Bernhard</creatorcontrib><creatorcontrib>Pabst, Caroline</creatorcontrib><creatorcontrib>Su, Le</creatorcontrib><creatorcontrib>Miller, Michelle</creatorcontrib><creatorcontrib>Liu, Feng</creatorcontrib><creatorcontrib>Yi, Lin</creatorcontrib><creatorcontrib>Zhang, Regan</creatorcontrib><creatorcontrib>Krosl, Jana</creatorcontrib><creatorcontrib>Yung, Eric</creatorcontrib><creatorcontrib>Kirschner, Jeanette</creatorcontrib><creatorcontrib>Rosten, Patty</creatorcontrib><creatorcontrib>Underhill, T Michael</creatorcontrib><creatorcontrib>Jin, Jian</creatorcontrib><creatorcontrib>Hébert, Josée</creatorcontrib><creatorcontrib>Sauvageau, Guy</creatorcontrib><creatorcontrib>Humphries, R Keith</creatorcontrib><creatorcontrib>Rossi, Fabio M</creatorcontrib><title>The methyltransferase G9a regulates HoxA9-dependent transcription in AML</title><title>Genes & development</title><addtitle>Genes Dev</addtitle><description>Chromatin modulators are emerging as attractive drug targets, given their widespread implication in human cancers and susceptibility to pharmacological inhibition. Here we establish the histone methyltransferase G9a/EHMT2 as a selective regulator of fast proliferating myeloid progenitors with no discernible function in hematopoietic stem cells (HSCs). In mouse models of acute myeloid leukemia (AML), loss of G9a significantly delays disease progression and reduces leukemia stem cell (LSC) frequency. We connect this function of G9a to its methyltransferase activity and its interaction with the leukemogenic transcription factor HoxA9 and provide evidence that primary human AML cells are sensitive to G9A inhibition. Our results highlight a clinical potential of G9A inhibition as a means to counteract the proliferation and self-renewal of AML cells by attenuating HoxA9-dependent transcription.</description><subject>Animals</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Cells, Cultured</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>HEK293 Cells</subject><subject>Hematopoietic Stem Cells - enzymology</subject><subject>Histone-Lysine N-Methyltransferase - genetics</subject><subject>Histone-Lysine N-Methyltransferase - metabolism</subject><subject>Homeodomain Proteins - metabolism</subject><subject>Humans</subject><subject>Leukemia, Myeloid, Acute - enzymology</subject><subject>Leukemia, Myeloid, Acute - genetics</subject><subject>Leukemia, Myeloid, Acute - pathology</subject><subject>Mice, Inbred C57BL</subject><subject>Quinazolines - pharmacology</subject><subject>Research Paper</subject><issn>0890-9369</issn><issn>1549-5477</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUT1PwzAUtBCIlsLKiDKypPj5M16QqgpapCKWMltu4rRB-cJOEP33uLRUMDE9nd690707hK4BjwEw3K1NNiZUSMUCpidoCJypmDMpT9EQJwrHigo1QBfev2GMBRbiHA0I45RIIEM0X25sVNlusy07Z2qfW2e8jWbKRM6u-9J01kfz5nOi4sy2ts5s3UXfzNQVbVc0dVTU0eR5cYnOclN6e3WYI_T6-LCczuPFy-xpOlnEKUtUF2e5gBxTLg0GQQhjmQTJDPAVlaCIokolhgouJBWWypXgCSjIc4IJkxlwOkL3e922X1U2S4MfZ0rduqIybqsbU-i_m7rY6HXzoamikoeMRuj2IOCa9976TleFT21Zmto2vdchQEwo5pD8T2VKBUvAd6rjPTV1jffO5kdHgPWuKR2a0vumAqbh4Ob3H0f6TzX0CxlAjSg</recordid><startdate>20140215</startdate><enddate>20140215</enddate><creator>Lehnertz, Bernhard</creator><creator>Pabst, Caroline</creator><creator>Su, Le</creator><creator>Miller, Michelle</creator><creator>Liu, Feng</creator><creator>Yi, Lin</creator><creator>Zhang, Regan</creator><creator>Krosl, Jana</creator><creator>Yung, Eric</creator><creator>Kirschner, Jeanette</creator><creator>Rosten, Patty</creator><creator>Underhill, T Michael</creator><creator>Jin, Jian</creator><creator>Hébert, Josée</creator><creator>Sauvageau, Guy</creator><creator>Humphries, R Keith</creator><creator>Rossi, Fabio M</creator><general>Cold Spring Harbor Laboratory Press</general><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>7X8</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20140215</creationdate><title>The methyltransferase G9a regulates HoxA9-dependent transcription in AML</title><author>Lehnertz, Bernhard ; Pabst, Caroline ; Su, Le ; Miller, Michelle ; Liu, Feng ; Yi, Lin ; Zhang, Regan ; Krosl, Jana ; Yung, Eric ; Kirschner, Jeanette ; Rosten, Patty ; Underhill, T Michael ; Jin, Jian ; Hébert, Josée ; Sauvageau, Guy ; Humphries, R Keith ; Rossi, Fabio M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c489t-df61f0357a0162244d7174a15b3719293998a3656736e37b658191ff20247d153</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Cells, Cultured</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>HEK293 Cells</topic><topic>Hematopoietic Stem Cells - enzymology</topic><topic>Histone-Lysine N-Methyltransferase - genetics</topic><topic>Histone-Lysine N-Methyltransferase - metabolism</topic><topic>Homeodomain Proteins - metabolism</topic><topic>Humans</topic><topic>Leukemia, Myeloid, Acute - enzymology</topic><topic>Leukemia, Myeloid, Acute - genetics</topic><topic>Leukemia, Myeloid, Acute - pathology</topic><topic>Mice, Inbred C57BL</topic><topic>Quinazolines - pharmacology</topic><topic>Research Paper</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lehnertz, Bernhard</creatorcontrib><creatorcontrib>Pabst, Caroline</creatorcontrib><creatorcontrib>Su, Le</creatorcontrib><creatorcontrib>Miller, Michelle</creatorcontrib><creatorcontrib>Liu, Feng</creatorcontrib><creatorcontrib>Yi, Lin</creatorcontrib><creatorcontrib>Zhang, Regan</creatorcontrib><creatorcontrib>Krosl, Jana</creatorcontrib><creatorcontrib>Yung, Eric</creatorcontrib><creatorcontrib>Kirschner, Jeanette</creatorcontrib><creatorcontrib>Rosten, Patty</creatorcontrib><creatorcontrib>Underhill, T Michael</creatorcontrib><creatorcontrib>Jin, Jian</creatorcontrib><creatorcontrib>Hébert, Josée</creatorcontrib><creatorcontrib>Sauvageau, Guy</creatorcontrib><creatorcontrib>Humphries, R Keith</creatorcontrib><creatorcontrib>Rossi, Fabio M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Genes & development</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lehnertz, Bernhard</au><au>Pabst, Caroline</au><au>Su, Le</au><au>Miller, Michelle</au><au>Liu, Feng</au><au>Yi, Lin</au><au>Zhang, Regan</au><au>Krosl, Jana</au><au>Yung, Eric</au><au>Kirschner, Jeanette</au><au>Rosten, Patty</au><au>Underhill, T Michael</au><au>Jin, Jian</au><au>Hébert, Josée</au><au>Sauvageau, Guy</au><au>Humphries, R Keith</au><au>Rossi, Fabio M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The methyltransferase G9a regulates HoxA9-dependent transcription in AML</atitle><jtitle>Genes & development</jtitle><addtitle>Genes Dev</addtitle><date>2014-02-15</date><risdate>2014</risdate><volume>28</volume><issue>4</issue><spage>317</spage><epage>327</epage><pages>317-327</pages><issn>0890-9369</issn><eissn>1549-5477</eissn><abstract>Chromatin modulators are emerging as attractive drug targets, given their widespread implication in human cancers and susceptibility to pharmacological inhibition. 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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Animals Cell Line, Tumor Cell Proliferation - drug effects Cells, Cultured Enzyme Inhibitors - pharmacology Gene Expression Regulation, Neoplastic HEK293 Cells Hematopoietic Stem Cells - enzymology Histone-Lysine N-Methyltransferase - genetics Histone-Lysine N-Methyltransferase - metabolism Homeodomain Proteins - metabolism Humans Leukemia, Myeloid, Acute - enzymology Leukemia, Myeloid, Acute - genetics Leukemia, Myeloid, Acute - pathology Mice, Inbred C57BL Quinazolines - pharmacology Research Paper |
| title | The methyltransferase G9a regulates HoxA9-dependent transcription in AML |
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