MLL5 Orchestrates a Cancer Self-Renewal State by Repressing the Histone Variant H3.3 and Globally Reorganizing Chromatin
Mutations in the histone 3 variant H3.3 have been identified in one-third of pediatric glioblastomas (GBMs), but not in adult tumors. Here we show that H3.3 is a dynamic determinant of functional properties in adult GBM. H3.3 is repressed by mixed lineage leukemia 5 (MLL5) in self-renewing GBM cells...
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| creator | Gallo, Marco Coutinho, Fiona J. Vanner, Robert J. Gayden, Tenzin Mack, Stephen C. Murison, Alex Remke, Marc Li, Ren Takayama, Naoya Desai, Kinjal Lee, Lilian Lan, Xiaoyang Park, Nicole I. Barsyte-Lovejoy, Dalia Smil, David Sturm, Dominik Kushida, Michelle M. Head, Renee Cusimano, Michael D. Bernstein, Mark Clarke, Ian D. Dick, John E. Pfister, Stefan M. Rich, Jeremy N. Arrowsmith, Cheryl H. Taylor, Michael D. Jabado, Nada Bazett-Jones, David P. Lupien, Mathieu Dirks, Peter B. |
| description | Mutations in the histone 3 variant H3.3 have been identified in one-third of pediatric glioblastomas (GBMs), but not in adult tumors. Here we show that H3.3 is a dynamic determinant of functional properties in adult GBM. H3.3 is repressed by mixed lineage leukemia 5 (MLL5) in self-renewing GBM cells. MLL5 is a global epigenetic repressor that orchestrates reorganization of chromatin structure by punctuating chromosomes with foci of compacted chromatin, favoring tumorigenic and self-renewing properties. Conversely, H3.3 antagonizes self-renewal and promotes differentiation. We exploited these epigenetic states to rationally identify two small molecules that effectively curb cancer stem cell properties in a preclinical model. Our work uncovers a role for MLL5 and H3.3 in maintaining self-renewal hierarchies in adult GBM.
[Display omitted]
•DNA methylomes of adult GBM self-renewing cells resemble H3.3-mutated pediatric GBM•MLL5 represses H3.3 levels in adult GBM self-renewing cells•MLL5 favors self-renewal and H3.3 favors differentiation in adult GBM•An MLL5/H3.3 signature predicted two compounds that curb GBM self-renewal
Gallo et al. show that MLL5 induces reorganization of chromatin structure and decreases expression of H3.3. Reduced H3.3 expression favors self-renewal properties of adult glioblastoma (GBM) cells and phenocopies pediatric GBM with H3.3 mutations, indicating potential therapeutic strategies for adult GBM. |
| doi_str_mv | 10.1016/j.ccell.2015.10.005 |
| format | Article |
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[Display omitted]
•DNA methylomes of adult GBM self-renewing cells resemble H3.3-mutated pediatric GBM•MLL5 represses H3.3 levels in adult GBM self-renewing cells•MLL5 favors self-renewal and H3.3 favors differentiation in adult GBM•An MLL5/H3.3 signature predicted two compounds that curb GBM self-renewal
Gallo et al. show that MLL5 induces reorganization of chromatin structure and decreases expression of H3.3. Reduced H3.3 expression favors self-renewal properties of adult glioblastoma (GBM) cells and phenocopies pediatric GBM with H3.3 mutations, indicating potential therapeutic strategies for adult GBM.</description><identifier>ISSN: 1535-6108</identifier><identifier>EISSN: 1878-3686</identifier><identifier>DOI: 10.1016/j.ccell.2015.10.005</identifier><identifier>PMID: 26626085</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adolescent ; Adult ; Animals ; Antineoplastic Agents - pharmacology ; Brain Neoplasms - drug therapy ; Brain Neoplasms - genetics ; Brain Neoplasms - metabolism ; Brain Neoplasms - mortality ; Brain Neoplasms - pathology ; Cell Differentiation ; Cell Proliferation ; Cell Self Renewal - drug effects ; Child ; Child, Preschool ; Chromatin Assembly and Disassembly - drug effects ; DNA Methylation ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Drug Design ; Epigenesis, Genetic ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Glioblastoma - drug therapy ; Glioblastoma - genetics ; Glioblastoma - metabolism ; Glioblastoma - mortality ; Glioblastoma - pathology ; Histones - genetics ; Histones - metabolism ; Humans ; Kaplan-Meier Estimate ; Mice, Inbred NOD ; Mice, SCID ; Molecular Targeted Therapy ; Mutation ; Neoplastic Stem Cells - drug effects ; Neoplastic Stem Cells - metabolism ; Neoplastic Stem Cells - pathology ; Prognosis ; RNA Interference ; Signal Transduction ; Time Factors ; Transfection ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays ; Young Adult</subject><ispartof>Cancer cell, 2015-12, Vol.28 (6), p.715-729</ispartof><rights>2015 Elsevier Inc.</rights><rights>Copyright © 2015 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c573t-5fd51e01ac6ae3c7009e676f28597c44e08c5d1ffbc0e08ff68ee5d583a4b79c3</citedby><cites>FETCH-LOGICAL-c573t-5fd51e01ac6ae3c7009e676f28597c44e08c5d1ffbc0e08ff68ee5d583a4b79c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1535610815003827$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26626085$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gallo, Marco</creatorcontrib><creatorcontrib>Coutinho, Fiona J.</creatorcontrib><creatorcontrib>Vanner, Robert J.</creatorcontrib><creatorcontrib>Gayden, Tenzin</creatorcontrib><creatorcontrib>Mack, Stephen C.</creatorcontrib><creatorcontrib>Murison, Alex</creatorcontrib><creatorcontrib>Remke, Marc</creatorcontrib><creatorcontrib>Li, Ren</creatorcontrib><creatorcontrib>Takayama, Naoya</creatorcontrib><creatorcontrib>Desai, Kinjal</creatorcontrib><creatorcontrib>Lee, Lilian</creatorcontrib><creatorcontrib>Lan, Xiaoyang</creatorcontrib><creatorcontrib>Park, Nicole I.</creatorcontrib><creatorcontrib>Barsyte-Lovejoy, Dalia</creatorcontrib><creatorcontrib>Smil, David</creatorcontrib><creatorcontrib>Sturm, Dominik</creatorcontrib><creatorcontrib>Kushida, Michelle M.</creatorcontrib><creatorcontrib>Head, Renee</creatorcontrib><creatorcontrib>Cusimano, Michael D.</creatorcontrib><creatorcontrib>Bernstein, Mark</creatorcontrib><creatorcontrib>Clarke, Ian D.</creatorcontrib><creatorcontrib>Dick, John E.</creatorcontrib><creatorcontrib>Pfister, Stefan M.</creatorcontrib><creatorcontrib>Rich, Jeremy N.</creatorcontrib><creatorcontrib>Arrowsmith, Cheryl H.</creatorcontrib><creatorcontrib>Taylor, Michael D.</creatorcontrib><creatorcontrib>Jabado, Nada</creatorcontrib><creatorcontrib>Bazett-Jones, David P.</creatorcontrib><creatorcontrib>Lupien, Mathieu</creatorcontrib><creatorcontrib>Dirks, Peter B.</creatorcontrib><title>MLL5 Orchestrates a Cancer Self-Renewal State by Repressing the Histone Variant H3.3 and Globally Reorganizing Chromatin</title><title>Cancer cell</title><addtitle>Cancer Cell</addtitle><description>Mutations in the histone 3 variant H3.3 have been identified in one-third of pediatric glioblastomas (GBMs), but not in adult tumors. Here we show that H3.3 is a dynamic determinant of functional properties in adult GBM. H3.3 is repressed by mixed lineage leukemia 5 (MLL5) in self-renewing GBM cells. MLL5 is a global epigenetic repressor that orchestrates reorganization of chromatin structure by punctuating chromosomes with foci of compacted chromatin, favoring tumorigenic and self-renewing properties. Conversely, H3.3 antagonizes self-renewal and promotes differentiation. We exploited these epigenetic states to rationally identify two small molecules that effectively curb cancer stem cell properties in a preclinical model. Our work uncovers a role for MLL5 and H3.3 in maintaining self-renewal hierarchies in adult GBM.
[Display omitted]
•DNA methylomes of adult GBM self-renewing cells resemble H3.3-mutated pediatric GBM•MLL5 represses H3.3 levels in adult GBM self-renewing cells•MLL5 favors self-renewal and H3.3 favors differentiation in adult GBM•An MLL5/H3.3 signature predicted two compounds that curb GBM self-renewal
Gallo et al. show that MLL5 induces reorganization of chromatin structure and decreases expression of H3.3. Reduced H3.3 expression favors self-renewal properties of adult glioblastoma (GBM) cells and phenocopies pediatric GBM with H3.3 mutations, indicating potential therapeutic strategies for adult GBM.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Brain Neoplasms - drug therapy</subject><subject>Brain Neoplasms - genetics</subject><subject>Brain Neoplasms - metabolism</subject><subject>Brain Neoplasms - mortality</subject><subject>Brain Neoplasms - pathology</subject><subject>Cell Differentiation</subject><subject>Cell Proliferation</subject><subject>Cell Self Renewal - drug effects</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Chromatin Assembly and Disassembly - drug effects</subject><subject>DNA Methylation</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Drug Design</subject><subject>Epigenesis, Genetic</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Glioblastoma - drug therapy</subject><subject>Glioblastoma - genetics</subject><subject>Glioblastoma - metabolism</subject><subject>Glioblastoma - mortality</subject><subject>Glioblastoma - pathology</subject><subject>Histones - genetics</subject><subject>Histones - metabolism</subject><subject>Humans</subject><subject>Kaplan-Meier Estimate</subject><subject>Mice, Inbred NOD</subject><subject>Mice, SCID</subject><subject>Molecular Targeted Therapy</subject><subject>Mutation</subject><subject>Neoplastic Stem Cells - drug effects</subject><subject>Neoplastic Stem Cells - metabolism</subject><subject>Neoplastic Stem Cells - pathology</subject><subject>Prognosis</subject><subject>RNA Interference</subject><subject>Signal Transduction</subject><subject>Time Factors</subject><subject>Transfection</subject><subject>Tumor Cells, Cultured</subject><subject>Xenograft Model Antitumor Assays</subject><subject>Young Adult</subject><issn>1535-6108</issn><issn>1878-3686</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkcFu1DAQhi0EoqX0CZCQj1wSxnHseA8c0Kp0kbaq1EKvluOMu15lncX2AuXpcdjSI-Lk0fj_PPJ8hLxhUDNg8v22thbHsW6AidKpAcQzcspUpyoulXxeasFFJRmoE_IqpS0UinWLl-SkkbKRoMQp-Xm1Xgt6He0GU44mY6KGLk2wGOktjq66wYA_zEhvc7mk_QO9wX3ElHy4p3mDdOVTngLSOxO9CZmueM2pCQO9HKfejOMMTPHeBP9rRpabOO1M9uE1eeHMmPD88TwjXz9dfFmuqvX15eflx3VlRcdzJdwgGAIzVhrktgNYoOyka5RYdLZtEZQVA3Out1Bq56RCFINQ3LR9t7D8jLw7vruP07dD-aTe-TTvzQScDkmzTqimVSDY_0Sh5U0roUT5MWrjlFJEp_fR70x80Az0bEdv9R87erYzN4udQr19HHDodzg8MX91lMCHYwDLRr57jDpZj0XG4CParIfJ_3PAb9_koS4</recordid><startdate>20151214</startdate><enddate>20151214</enddate><creator>Gallo, Marco</creator><creator>Coutinho, Fiona J.</creator><creator>Vanner, Robert J.</creator><creator>Gayden, Tenzin</creator><creator>Mack, Stephen C.</creator><creator>Murison, Alex</creator><creator>Remke, Marc</creator><creator>Li, Ren</creator><creator>Takayama, Naoya</creator><creator>Desai, Kinjal</creator><creator>Lee, Lilian</creator><creator>Lan, Xiaoyang</creator><creator>Park, Nicole I.</creator><creator>Barsyte-Lovejoy, Dalia</creator><creator>Smil, David</creator><creator>Sturm, Dominik</creator><creator>Kushida, Michelle M.</creator><creator>Head, Renee</creator><creator>Cusimano, Michael D.</creator><creator>Bernstein, Mark</creator><creator>Clarke, Ian D.</creator><creator>Dick, John E.</creator><creator>Pfister, Stefan M.</creator><creator>Rich, Jeremy N.</creator><creator>Arrowsmith, Cheryl H.</creator><creator>Taylor, Michael D.</creator><creator>Jabado, Nada</creator><creator>Bazett-Jones, David P.</creator><creator>Lupien, Mathieu</creator><creator>Dirks, Peter B.</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>7X8</scope><scope>7TO</scope><scope>H94</scope></search><sort><creationdate>20151214</creationdate><title>MLL5 Orchestrates a Cancer Self-Renewal State by Repressing the Histone Variant H3.3 and Globally Reorganizing Chromatin</title><author>Gallo, Marco ; Coutinho, Fiona J. ; Vanner, Robert J. ; Gayden, Tenzin ; Mack, Stephen C. ; Murison, Alex ; Remke, Marc ; Li, Ren ; Takayama, Naoya ; Desai, Kinjal ; Lee, Lilian ; Lan, Xiaoyang ; Park, Nicole I. ; Barsyte-Lovejoy, Dalia ; Smil, David ; Sturm, Dominik ; Kushida, Michelle M. ; Head, Renee ; Cusimano, Michael D. ; Bernstein, Mark ; Clarke, Ian D. ; Dick, John E. ; Pfister, Stefan M. ; Rich, Jeremy N. ; Arrowsmith, Cheryl H. ; Taylor, Michael D. ; Jabado, Nada ; Bazett-Jones, David P. ; Lupien, Mathieu ; Dirks, Peter B.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c573t-5fd51e01ac6ae3c7009e676f28597c44e08c5d1ffbc0e08ff68ee5d583a4b79c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Animals</topic><topic>Antineoplastic Agents - 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Here we show that H3.3 is a dynamic determinant of functional properties in adult GBM. H3.3 is repressed by mixed lineage leukemia 5 (MLL5) in self-renewing GBM cells. MLL5 is a global epigenetic repressor that orchestrates reorganization of chromatin structure by punctuating chromosomes with foci of compacted chromatin, favoring tumorigenic and self-renewing properties. Conversely, H3.3 antagonizes self-renewal and promotes differentiation. We exploited these epigenetic states to rationally identify two small molecules that effectively curb cancer stem cell properties in a preclinical model. Our work uncovers a role for MLL5 and H3.3 in maintaining self-renewal hierarchies in adult GBM.
[Display omitted]
•DNA methylomes of adult GBM self-renewing cells resemble H3.3-mutated pediatric GBM•MLL5 represses H3.3 levels in adult GBM self-renewing cells•MLL5 favors self-renewal and H3.3 favors differentiation in adult GBM•An MLL5/H3.3 signature predicted two compounds that curb GBM self-renewal
Gallo et al. show that MLL5 induces reorganization of chromatin structure and decreases expression of H3.3. Reduced H3.3 expression favors self-renewal properties of adult glioblastoma (GBM) cells and phenocopies pediatric GBM with H3.3 mutations, indicating potential therapeutic strategies for adult GBM.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>26626085</pmid><doi>10.1016/j.ccell.2015.10.005</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1535-6108 |
| ispartof | Cancer cell, 2015-12, Vol.28 (6), p.715-729 |
| issn | 1535-6108 1878-3686 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1758248051 |
| source | MEDLINE; Cell Press Free Archives; Elsevier ScienceDirect Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Adolescent Adult Animals Antineoplastic Agents - pharmacology Brain Neoplasms - drug therapy Brain Neoplasms - genetics Brain Neoplasms - metabolism Brain Neoplasms - mortality Brain Neoplasms - pathology Cell Differentiation Cell Proliferation Cell Self Renewal - drug effects Child Child, Preschool Chromatin Assembly and Disassembly - drug effects DNA Methylation DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Drug Design Epigenesis, Genetic Gene Expression Profiling Gene Expression Regulation, Neoplastic Glioblastoma - drug therapy Glioblastoma - genetics Glioblastoma - metabolism Glioblastoma - mortality Glioblastoma - pathology Histones - genetics Histones - metabolism Humans Kaplan-Meier Estimate Mice, Inbred NOD Mice, SCID Molecular Targeted Therapy Mutation Neoplastic Stem Cells - drug effects Neoplastic Stem Cells - metabolism Neoplastic Stem Cells - pathology Prognosis RNA Interference Signal Transduction Time Factors Transfection Tumor Cells, Cultured Xenograft Model Antitumor Assays Young Adult |
| title | MLL5 Orchestrates a Cancer Self-Renewal State by Repressing the Histone Variant H3.3 and Globally Reorganizing Chromatin |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T16%3A35%3A17IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=MLL5%20Orchestrates%20a%20Cancer%20Self-Renewal%20State%20by%20Repressing%20the%20Histone%20Variant%20H3.3%20and%20Globally%20Reorganizing%20Chromatin&rft.jtitle=Cancer%20cell&rft.au=Gallo,%20Marco&rft.date=2015-12-14&rft.volume=28&rft.issue=6&rft.spage=715&rft.epage=729&rft.pages=715-729&rft.issn=1535-6108&rft.eissn=1878-3686&rft_id=info:doi/10.1016/j.ccell.2015.10.005&rft_dat=%3Cproquest_cross%3E1758248051%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1750432460&rft_id=info:pmid/26626085&rft_els_id=S1535610815003827&rfr_iscdi=true |