CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300-mutated lymphomas
Somatic mutations affecting CREBBP and EP300 are a hallmark of diffuse large B-cell lymphoma (DLBCL). These mutations are frequently monoallelic, within the histone acetyltransferase (HAT) domain and usually mutually exclusive, suggesting that they might affect a common pathway, and their residual W...
Gespeichert in:
| Veröffentlicht in: | Leukemia 2020-12, Vol.34 (12), p.3269-3285 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 3285 |
|---|---|
| container_issue | 12 |
| container_start_page | 3269 |
| container_title | Leukemia |
| container_volume | 34 |
| creator | Veazey, Kylee J. Cheng, Donghang Lin, Kevin Villarreal, Oscar D. Gao, Guozhen Perez-Oquendo, Mabel Van, Hieu T. Stratton, Sabrina A. Green, Michael Xu, Han Lu, Yue Bedford, Mark T. Santos, Margarida Almeida |
| description | Somatic mutations affecting
CREBBP
and
EP300
are a hallmark of diffuse large B-cell lymphoma (DLBCL). These mutations are frequently monoallelic, within the histone acetyltransferase (HAT) domain and usually mutually exclusive, suggesting that they might affect a common pathway, and their residual WT expression is required for cell survival. Using in vitro and in vivo models, we found that inhibition of CARM1 activity (CARM1i) slows DLBCL growth, and that the levels of sensitivity are positively correlated with the
CREBBP/EP300
mutation load. Conversely, treatment of DLBCLs that do not have
CREBBP/EP300
mutations with CARM1i and a CBP/p300 inhibitor revealed a strong synergistic effect. Our mechanistic data show that CARM1i further reduces the HAT activity of CBP genome wide and downregulates CBP-target genes in DLBCL cells, resulting in a synthetic lethality that leverages the mutational status of
CREBBP/EP300
as a biomarker for the use of small-molecule inhibitors of CARM1 in DLBCL and other cancers. |
| doi_str_mv | 10.1038/s41375-020-0908-8 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7688486</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A650886449</galeid><sourcerecordid>A650886449</sourcerecordid><originalsourceid>FETCH-LOGICAL-c5538-85a2722f0b271a3858c3595a0829962ad0ee7a4b2041dd1143ec5026ac14a1b43</originalsourceid><addsrcrecordid>eNp1UltrFDEYDaLYtfoDfJEBwbdpc5_Mi7Bd1ipULEWfQyaT2UmZSdYkU5h_b6Zb2y4oeQjkXMj5vgPAewTPECTiPFJEKlZCDEtYQ1GKF2CFaMVLxhh6CVZQiKrkNaYn4E2MtxAuIH8NTghmFa85XoF5s775jgrretvYZL0rgmknbWLR25i8M4XSJs1DCsrFzgQVl5dk72yaC62maN2uiLNLvUlWF4NJvRoWzLpic7O9uLg-314TCMtxSiqZthjmcd_7UcW34FWnhmjePdyn4NeX7c_N1_Lqx-W3zfqq1IyRnIkpXGHcwQZXSBHBhCasZgoKXOcEqoXGVIo2GFLUtghRYjSDmCuNqEINJafg88F3PzWjabVxOcsg98GOKszSKyuPEWd7ufN3suJCUMGzwccHg-B_TyYmeeun4PKfJaYVwRgSWj-xdmow0rrOZzM92qjlmrO8CU7vWWf_YOXTmtHqPO7O5vcjwadngt6oIfXRD9OyqnhMRAeiDj7GYLrHhAjKpS3y0BaZ2yKXtkiRNR-ej-ZR8bcemYAPhJghtzPhKfr_Xf8Aa7TJXg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2473220349</pqid></control><display><type>article</type><title>CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300-mutated lymphomas</title><source>MEDLINE</source><source>Alma/SFX Local Collection</source><creator>Veazey, Kylee J. ; Cheng, Donghang ; Lin, Kevin ; Villarreal, Oscar D. ; Gao, Guozhen ; Perez-Oquendo, Mabel ; Van, Hieu T. ; Stratton, Sabrina A. ; Green, Michael ; Xu, Han ; Lu, Yue ; Bedford, Mark T. ; Santos, Margarida Almeida</creator><creatorcontrib>Veazey, Kylee J. ; Cheng, Donghang ; Lin, Kevin ; Villarreal, Oscar D. ; Gao, Guozhen ; Perez-Oquendo, Mabel ; Van, Hieu T. ; Stratton, Sabrina A. ; Green, Michael ; Xu, Han ; Lu, Yue ; Bedford, Mark T. ; Santos, Margarida Almeida</creatorcontrib><description>Somatic mutations affecting
CREBBP
and
EP300
are a hallmark of diffuse large B-cell lymphoma (DLBCL). These mutations are frequently monoallelic, within the histone acetyltransferase (HAT) domain and usually mutually exclusive, suggesting that they might affect a common pathway, and their residual WT expression is required for cell survival. Using in vitro and in vivo models, we found that inhibition of CARM1 activity (CARM1i) slows DLBCL growth, and that the levels of sensitivity are positively correlated with the
CREBBP/EP300
mutation load. Conversely, treatment of DLBCLs that do not have
CREBBP/EP300
mutations with CARM1i and a CBP/p300 inhibitor revealed a strong synergistic effect. Our mechanistic data show that CARM1i further reduces the HAT activity of CBP genome wide and downregulates CBP-target genes in DLBCL cells, resulting in a synthetic lethality that leverages the mutational status of
CREBBP/EP300
as a biomarker for the use of small-molecule inhibitors of CARM1 in DLBCL and other cancers.</description><identifier>ISSN: 0887-6924</identifier><identifier>EISSN: 1476-5551</identifier><identifier>DOI: 10.1038/s41375-020-0908-8</identifier><identifier>PMID: 32576962</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/106 ; 13/31 ; 45/15 ; 45/91 ; 631/67/1990/291/1621/1915 ; 631/67/68/2486 ; 64/60 ; Acetylation - drug effects ; Animals ; B-cell lymphoma ; Biological markers ; Biomarkers ; Cancer Research ; Care and treatment ; Cell Line ; Cell survival ; CREB-Binding Protein - genetics ; Critical Care Medicine ; Development and progression ; Down-Regulation - genetics ; E1A-Associated p300 Protein - genetics ; Gene mutations ; Genetic aspects ; Genomes ; Health aspects ; Hematology ; Histone acetyltransferase ; Histone Acetyltransferases - metabolism ; Histones ; Identification and classification ; Intensive ; Internal Medicine ; Lethality ; Lymphocytes B ; Lymphoma ; Lymphoma, Large B-Cell, Diffuse - genetics ; Lymphoma, Large B-Cell, Diffuse - metabolism ; Lymphomas ; Medicine ; Medicine & Public Health ; Methyltransferases ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Mutation ; Oncology ; Protein-Arginine N-Methyltransferases - antagonists & inhibitors ; Synergistic effect ; Synthetic Lethal Mutations - genetics</subject><ispartof>Leukemia, 2020-12, Vol.34 (12), p.3269-3285</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2020</rights><rights>COPYRIGHT 2020 Nature Publishing Group</rights><rights>The Author(s), under exclusive licence to Springer Nature Limited 2020.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5538-85a2722f0b271a3858c3595a0829962ad0ee7a4b2041dd1143ec5026ac14a1b43</citedby><cites>FETCH-LOGICAL-c5538-85a2722f0b271a3858c3595a0829962ad0ee7a4b2041dd1143ec5026ac14a1b43</cites><orcidid>0000-0001-6309-9472 ; 0000-0001-6043-0852 ; 0000-0002-9510-1474 ; 0000-0001-9065-0733</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32576962$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Veazey, Kylee J.</creatorcontrib><creatorcontrib>Cheng, Donghang</creatorcontrib><creatorcontrib>Lin, Kevin</creatorcontrib><creatorcontrib>Villarreal, Oscar D.</creatorcontrib><creatorcontrib>Gao, Guozhen</creatorcontrib><creatorcontrib>Perez-Oquendo, Mabel</creatorcontrib><creatorcontrib>Van, Hieu T.</creatorcontrib><creatorcontrib>Stratton, Sabrina A.</creatorcontrib><creatorcontrib>Green, Michael</creatorcontrib><creatorcontrib>Xu, Han</creatorcontrib><creatorcontrib>Lu, Yue</creatorcontrib><creatorcontrib>Bedford, Mark T.</creatorcontrib><creatorcontrib>Santos, Margarida Almeida</creatorcontrib><title>CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300-mutated lymphomas</title><title>Leukemia</title><addtitle>Leukemia</addtitle><addtitle>Leukemia</addtitle><description>Somatic mutations affecting
CREBBP
and
EP300
are a hallmark of diffuse large B-cell lymphoma (DLBCL). These mutations are frequently monoallelic, within the histone acetyltransferase (HAT) domain and usually mutually exclusive, suggesting that they might affect a common pathway, and their residual WT expression is required for cell survival. Using in vitro and in vivo models, we found that inhibition of CARM1 activity (CARM1i) slows DLBCL growth, and that the levels of sensitivity are positively correlated with the
CREBBP/EP300
mutation load. Conversely, treatment of DLBCLs that do not have
CREBBP/EP300
mutations with CARM1i and a CBP/p300 inhibitor revealed a strong synergistic effect. Our mechanistic data show that CARM1i further reduces the HAT activity of CBP genome wide and downregulates CBP-target genes in DLBCL cells, resulting in a synthetic lethality that leverages the mutational status of
CREBBP/EP300
as a biomarker for the use of small-molecule inhibitors of CARM1 in DLBCL and other cancers.</description><subject>13/106</subject><subject>13/31</subject><subject>45/15</subject><subject>45/91</subject><subject>631/67/1990/291/1621/1915</subject><subject>631/67/68/2486</subject><subject>64/60</subject><subject>Acetylation - drug effects</subject><subject>Animals</subject><subject>B-cell lymphoma</subject><subject>Biological markers</subject><subject>Biomarkers</subject><subject>Cancer Research</subject><subject>Care and treatment</subject><subject>Cell Line</subject><subject>Cell survival</subject><subject>CREB-Binding Protein - genetics</subject><subject>Critical Care Medicine</subject><subject>Development and progression</subject><subject>Down-Regulation - genetics</subject><subject>E1A-Associated p300 Protein - genetics</subject><subject>Gene mutations</subject><subject>Genetic aspects</subject><subject>Genomes</subject><subject>Health aspects</subject><subject>Hematology</subject><subject>Histone acetyltransferase</subject><subject>Histone Acetyltransferases - metabolism</subject><subject>Histones</subject><subject>Identification and classification</subject><subject>Intensive</subject><subject>Internal Medicine</subject><subject>Lethality</subject><subject>Lymphocytes B</subject><subject>Lymphoma</subject><subject>Lymphoma, Large B-Cell, Diffuse - genetics</subject><subject>Lymphoma, Large B-Cell, Diffuse - metabolism</subject><subject>Lymphomas</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Methyltransferases</subject><subject>Mice</subject><subject>Mice, Inbred NOD</subject><subject>Mice, SCID</subject><subject>Mutation</subject><subject>Oncology</subject><subject>Protein-Arginine N-Methyltransferases - antagonists & inhibitors</subject><subject>Synergistic effect</subject><subject>Synthetic Lethal Mutations - genetics</subject><issn>0887-6924</issn><issn>1476-5551</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp1UltrFDEYDaLYtfoDfJEBwbdpc5_Mi7Bd1ipULEWfQyaT2UmZSdYkU5h_b6Zb2y4oeQjkXMj5vgPAewTPECTiPFJEKlZCDEtYQ1GKF2CFaMVLxhh6CVZQiKrkNaYn4E2MtxAuIH8NTghmFa85XoF5s775jgrretvYZL0rgmknbWLR25i8M4XSJs1DCsrFzgQVl5dk72yaC62maN2uiLNLvUlWF4NJvRoWzLpic7O9uLg-314TCMtxSiqZthjmcd_7UcW34FWnhmjePdyn4NeX7c_N1_Lqx-W3zfqq1IyRnIkpXGHcwQZXSBHBhCasZgoKXOcEqoXGVIo2GFLUtghRYjSDmCuNqEINJafg88F3PzWjabVxOcsg98GOKszSKyuPEWd7ufN3suJCUMGzwccHg-B_TyYmeeun4PKfJaYVwRgSWj-xdmow0rrOZzM92qjlmrO8CU7vWWf_YOXTmtHqPO7O5vcjwadngt6oIfXRD9OyqnhMRAeiDj7GYLrHhAjKpS3y0BaZ2yKXtkiRNR-ej-ZR8bcemYAPhJghtzPhKfr_Xf8Aa7TJXg</recordid><startdate>20201201</startdate><enddate>20201201</enddate><creator>Veazey, Kylee J.</creator><creator>Cheng, Donghang</creator><creator>Lin, Kevin</creator><creator>Villarreal, Oscar D.</creator><creator>Gao, Guozhen</creator><creator>Perez-Oquendo, Mabel</creator><creator>Van, Hieu T.</creator><creator>Stratton, Sabrina A.</creator><creator>Green, Michael</creator><creator>Xu, Han</creator><creator>Lu, Yue</creator><creator>Bedford, Mark T.</creator><creator>Santos, Margarida Almeida</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</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>3V.</scope><scope>7QL</scope><scope>7RV</scope><scope>7T5</scope><scope>7T7</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-6309-9472</orcidid><orcidid>https://orcid.org/0000-0001-6043-0852</orcidid><orcidid>https://orcid.org/0000-0002-9510-1474</orcidid><orcidid>https://orcid.org/0000-0001-9065-0733</orcidid></search><sort><creationdate>20201201</creationdate><title>CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300-mutated lymphomas</title><author>Veazey, Kylee J. ; Cheng, Donghang ; Lin, Kevin ; Villarreal, Oscar D. ; Gao, Guozhen ; Perez-Oquendo, Mabel ; Van, Hieu T. ; Stratton, Sabrina A. ; Green, Michael ; Xu, Han ; Lu, Yue ; Bedford, Mark T. ; Santos, Margarida Almeida</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5538-85a2722f0b271a3858c3595a0829962ad0ee7a4b2041dd1143ec5026ac14a1b43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>13/106</topic><topic>13/31</topic><topic>45/15</topic><topic>45/91</topic><topic>631/67/1990/291/1621/1915</topic><topic>631/67/68/2486</topic><topic>64/60</topic><topic>Acetylation - drug effects</topic><topic>Animals</topic><topic>B-cell lymphoma</topic><topic>Biological markers</topic><topic>Biomarkers</topic><topic>Cancer Research</topic><topic>Care and treatment</topic><topic>Cell Line</topic><topic>Cell survival</topic><topic>CREB-Binding Protein - genetics</topic><topic>Critical Care Medicine</topic><topic>Development and progression</topic><topic>Down-Regulation - genetics</topic><topic>E1A-Associated p300 Protein - genetics</topic><topic>Gene mutations</topic><topic>Genetic aspects</topic><topic>Genomes</topic><topic>Health aspects</topic><topic>Hematology</topic><topic>Histone acetyltransferase</topic><topic>Histone Acetyltransferases - metabolism</topic><topic>Histones</topic><topic>Identification and classification</topic><topic>Intensive</topic><topic>Internal Medicine</topic><topic>Lethality</topic><topic>Lymphocytes B</topic><topic>Lymphoma</topic><topic>Lymphoma, Large B-Cell, Diffuse - genetics</topic><topic>Lymphoma, Large B-Cell, Diffuse - metabolism</topic><topic>Lymphomas</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Methyltransferases</topic><topic>Mice</topic><topic>Mice, Inbred NOD</topic><topic>Mice, SCID</topic><topic>Mutation</topic><topic>Oncology</topic><topic>Protein-Arginine N-Methyltransferases - antagonists & inhibitors</topic><topic>Synergistic effect</topic><topic>Synthetic Lethal Mutations - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Veazey, Kylee J.</creatorcontrib><creatorcontrib>Cheng, Donghang</creatorcontrib><creatorcontrib>Lin, Kevin</creatorcontrib><creatorcontrib>Villarreal, Oscar D.</creatorcontrib><creatorcontrib>Gao, Guozhen</creatorcontrib><creatorcontrib>Perez-Oquendo, Mabel</creatorcontrib><creatorcontrib>Van, Hieu T.</creatorcontrib><creatorcontrib>Stratton, Sabrina A.</creatorcontrib><creatorcontrib>Green, Michael</creatorcontrib><creatorcontrib>Xu, Han</creatorcontrib><creatorcontrib>Lu, Yue</creatorcontrib><creatorcontrib>Bedford, Mark T.</creatorcontrib><creatorcontrib>Santos, Margarida Almeida</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Nursing & Allied Health Database</collection><collection>Immunology Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Leukemia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Veazey, Kylee J.</au><au>Cheng, Donghang</au><au>Lin, Kevin</au><au>Villarreal, Oscar D.</au><au>Gao, Guozhen</au><au>Perez-Oquendo, Mabel</au><au>Van, Hieu T.</au><au>Stratton, Sabrina A.</au><au>Green, Michael</au><au>Xu, Han</au><au>Lu, Yue</au><au>Bedford, Mark T.</au><au>Santos, Margarida Almeida</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300-mutated lymphomas</atitle><jtitle>Leukemia</jtitle><stitle>Leukemia</stitle><addtitle>Leukemia</addtitle><date>2020-12-01</date><risdate>2020</risdate><volume>34</volume><issue>12</issue><spage>3269</spage><epage>3285</epage><pages>3269-3285</pages><issn>0887-6924</issn><eissn>1476-5551</eissn><abstract>Somatic mutations affecting
CREBBP
and
EP300
are a hallmark of diffuse large B-cell lymphoma (DLBCL). These mutations are frequently monoallelic, within the histone acetyltransferase (HAT) domain and usually mutually exclusive, suggesting that they might affect a common pathway, and their residual WT expression is required for cell survival. Using in vitro and in vivo models, we found that inhibition of CARM1 activity (CARM1i) slows DLBCL growth, and that the levels of sensitivity are positively correlated with the
CREBBP/EP300
mutation load. Conversely, treatment of DLBCLs that do not have
CREBBP/EP300
mutations with CARM1i and a CBP/p300 inhibitor revealed a strong synergistic effect. Our mechanistic data show that CARM1i further reduces the HAT activity of CBP genome wide and downregulates CBP-target genes in DLBCL cells, resulting in a synthetic lethality that leverages the mutational status of
CREBBP/EP300
as a biomarker for the use of small-molecule inhibitors of CARM1 in DLBCL and other cancers.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>32576962</pmid><doi>10.1038/s41375-020-0908-8</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0001-6309-9472</orcidid><orcidid>https://orcid.org/0000-0001-6043-0852</orcidid><orcidid>https://orcid.org/0000-0002-9510-1474</orcidid><orcidid>https://orcid.org/0000-0001-9065-0733</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0887-6924 |
| ispartof | Leukemia, 2020-12, Vol.34 (12), p.3269-3285 |
| issn | 0887-6924 1476-5551 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7688486 |
| source | MEDLINE; Alma/SFX Local Collection |
| subjects | 13/106 13/31 45/15 45/91 631/67/1990/291/1621/1915 631/67/68/2486 64/60 Acetylation - drug effects Animals B-cell lymphoma Biological markers Biomarkers Cancer Research Care and treatment Cell Line Cell survival CREB-Binding Protein - genetics Critical Care Medicine Development and progression Down-Regulation - genetics E1A-Associated p300 Protein - genetics Gene mutations Genetic aspects Genomes Health aspects Hematology Histone acetyltransferase Histone Acetyltransferases - metabolism Histones Identification and classification Intensive Internal Medicine Lethality Lymphocytes B Lymphoma Lymphoma, Large B-Cell, Diffuse - genetics Lymphoma, Large B-Cell, Diffuse - metabolism Lymphomas Medicine Medicine & Public Health Methyltransferases Mice Mice, Inbred NOD Mice, SCID Mutation Oncology Protein-Arginine N-Methyltransferases - antagonists & inhibitors Synergistic effect Synthetic Lethal Mutations - genetics |
| title | CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300-mutated lymphomas |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-21T03%3A26%3A01IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=CARM1%20inhibition%20reduces%20histone%20acetyltransferase%20activity%20causing%20synthetic%20lethality%20in%20CREBBP/EP300-mutated%20lymphomas&rft.jtitle=Leukemia&rft.au=Veazey,%20Kylee%20J.&rft.date=2020-12-01&rft.volume=34&rft.issue=12&rft.spage=3269&rft.epage=3285&rft.pages=3269-3285&rft.issn=0887-6924&rft.eissn=1476-5551&rft_id=info:doi/10.1038/s41375-020-0908-8&rft_dat=%3Cgale_pubme%3EA650886449%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2473220349&rft_id=info:pmid/32576962&rft_galeid=A650886449&rfr_iscdi=true |