Disruption of the MYC Superenhancer Complex by Dual Targeting of FLT3 and LSD1 in Acute Myeloid Leukemia
Mutations in Fms-like tyrosine kinase 3 (FLT3) are common drivers in acute myeloid leukemia (AML) yet FLT3 inhibitors only provide modest clinical benefit. Prior work has shown that inhibitors of lysine-specific demethylase 1 (LSD1) enhance kinase inhibitor activity in AML. Here we show that combine...
Gespeichert in:
| Veröffentlicht in: | Molecular cancer research 2023-07, Vol.21 (7), p.631-647 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 647 |
|---|---|
| container_issue | 7 |
| container_start_page | 631 |
| container_title | Molecular cancer research |
| container_volume | 21 |
| creator | Yashar, William M Curtiss, Brittany M Coleman, Daniel J VanCampen, Jake Kong, Garth Macaraeg, Jommel Estabrook, Joseph Demir, Emek Long, Nicola Bottomly, Daniel McWeeney, Shannon K Tyner, Jeffrey W Druker, Brian J Maxson, Julia E Braun, Theodore P |
| description | Mutations in Fms-like tyrosine kinase 3 (FLT3) are common drivers in acute myeloid leukemia (AML) yet FLT3 inhibitors only provide modest clinical benefit. Prior work has shown that inhibitors of lysine-specific demethylase 1 (LSD1) enhance kinase inhibitor activity in AML. Here we show that combined LSD1 and FLT3 inhibition induces synergistic cell death in FLT3-mutant AML. Multi-omic profiling revealed that the drug combination disrupts STAT5, LSD1, and GFI1 binding at the MYC blood superenhancer, suppressing superenhancer accessibility as well as MYC expression and activity. The drug combination simultaneously results in the accumulation of repressive H3K9me1 methylation, an LSD1 substrate, at MYC target genes. We validated these findings in 72 primary AML samples with the nearly every sample demonstrating synergistic responses to the drug combination. Collectively, these studies reveal how epigenetic therapies augment the activity of kinase inhibitors in FLT3-ITD (internal tandem duplication) AML.
This work establishes the synergistic efficacy of combined FLT3 and LSD1 inhibition in FLT3-ITD AML by disrupting STAT5 and GFI1 binding at the MYC blood-specific superenhancer complex. |
| doi_str_mv | 10.1158/1541-7786.MCR-22-0745 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2833646759</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2833646759</sourcerecordid><originalsourceid>FETCH-LOGICAL-c356t-f6cf9e8b514ab10bc8d788efe6dad7519a8374614f917ad5f8917ca6d5f303f23</originalsourceid><addsrcrecordid>eNo9kMtOwzAURC0EouXxCSAv2aTEdvzIskopIAUhQVmwspzkmgbywk4k-vckamE1o6uZudJB6IqEC0K4uiU8IoGUSiyekpeA0iCUET9Cc8K5DBih_Hjyh8wMnXn_GYY0JFKcohkTsRSMsjnarkrvhq4v2wa3FvdbwE_vCX4dOnDQbE2Tg8NJW3cV_OBsh1eDqfDGuA_oy-ZjqqzTDcOmKXD6uiK4bPAyH_pxZQdVW45XGL6gLs0FOrGm8nB50HP0tr7bJA9B-nz_mCzTIGdc9IEVuY1BZZxEJiNhlqtCKgUWRGEKyUlsFJORIJGNiTQFt2rU3IjRsZBZys7RzX63c-33AL7XdelzqCrTQDt4TRVjIhKSx2OU76O5a713YHXnytq4nSahniDrCaCeAOoRsqZUT5DH3vXhxZDVUPy3_qiyX_hBd0M</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2833646759</pqid></control><display><type>article</type><title>Disruption of the MYC Superenhancer Complex by Dual Targeting of FLT3 and LSD1 in Acute Myeloid Leukemia</title><source>MEDLINE</source><source>American Association for Cancer Research</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Free Full-Text Journals in Chemistry</source><creator>Yashar, William M ; Curtiss, Brittany M ; Coleman, Daniel J ; VanCampen, Jake ; Kong, Garth ; Macaraeg, Jommel ; Estabrook, Joseph ; Demir, Emek ; Long, Nicola ; Bottomly, Daniel ; McWeeney, Shannon K ; Tyner, Jeffrey W ; Druker, Brian J ; Maxson, Julia E ; Braun, Theodore P</creator><creatorcontrib>Yashar, William M ; Curtiss, Brittany M ; Coleman, Daniel J ; VanCampen, Jake ; Kong, Garth ; Macaraeg, Jommel ; Estabrook, Joseph ; Demir, Emek ; Long, Nicola ; Bottomly, Daniel ; McWeeney, Shannon K ; Tyner, Jeffrey W ; Druker, Brian J ; Maxson, Julia E ; Braun, Theodore P</creatorcontrib><description>Mutations in Fms-like tyrosine kinase 3 (FLT3) are common drivers in acute myeloid leukemia (AML) yet FLT3 inhibitors only provide modest clinical benefit. Prior work has shown that inhibitors of lysine-specific demethylase 1 (LSD1) enhance kinase inhibitor activity in AML. Here we show that combined LSD1 and FLT3 inhibition induces synergistic cell death in FLT3-mutant AML. Multi-omic profiling revealed that the drug combination disrupts STAT5, LSD1, and GFI1 binding at the MYC blood superenhancer, suppressing superenhancer accessibility as well as MYC expression and activity. The drug combination simultaneously results in the accumulation of repressive H3K9me1 methylation, an LSD1 substrate, at MYC target genes. We validated these findings in 72 primary AML samples with the nearly every sample demonstrating synergistic responses to the drug combination. Collectively, these studies reveal how epigenetic therapies augment the activity of kinase inhibitors in FLT3-ITD (internal tandem duplication) AML.
This work establishes the synergistic efficacy of combined FLT3 and LSD1 inhibition in FLT3-ITD AML by disrupting STAT5 and GFI1 binding at the MYC blood-specific superenhancer complex.</description><identifier>ISSN: 1541-7786</identifier><identifier>EISSN: 1557-3125</identifier><identifier>DOI: 10.1158/1541-7786.MCR-22-0745</identifier><identifier>PMID: 36976323</identifier><language>eng</language><publisher>United States</publisher><subject>Apoptosis ; fms-Like Tyrosine Kinase 3 - genetics ; fms-Like Tyrosine Kinase 3 - metabolism ; Histone Demethylases - genetics ; Histone Demethylases - metabolism ; Humans ; Leukemia, Myeloid, Acute - drug therapy ; Leukemia, Myeloid, Acute - genetics ; Leukemia, Myeloid, Acute - metabolism ; Mutation ; Protein Kinase Inhibitors - pharmacology ; Protein Kinase Inhibitors - therapeutic use ; STAT5 Transcription Factor - metabolism</subject><ispartof>Molecular cancer research, 2023-07, Vol.21 (7), p.631-647</ispartof><rights>2023 American Association for Cancer Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-f6cf9e8b514ab10bc8d788efe6dad7519a8374614f917ad5f8917ca6d5f303f23</citedby><cites>FETCH-LOGICAL-c356t-f6cf9e8b514ab10bc8d788efe6dad7519a8374614f917ad5f8917ca6d5f303f23</cites><orcidid>0000-0001-8333-6607 ; 0000-0003-1361-0927 ; 0000-0001-8331-8206 ; 0000-0002-6307-5056 ; 0000-0002-8850-9850 ; 0000-0002-5274-8323 ; 0000-0002-3414-3160 ; 0000-0002-3871-7221 ; 0000-0002-2133-0960 ; 0000-0002-3663-7113 ; 0000-0002-6248-2143 ; 0000-0002-9010-8167 ; 0000-0002-1027-3315 ; 0000-0001-7191-0990 ; 0000-0001-5262-5406</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,3356,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36976323$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yashar, William M</creatorcontrib><creatorcontrib>Curtiss, Brittany M</creatorcontrib><creatorcontrib>Coleman, Daniel J</creatorcontrib><creatorcontrib>VanCampen, Jake</creatorcontrib><creatorcontrib>Kong, Garth</creatorcontrib><creatorcontrib>Macaraeg, Jommel</creatorcontrib><creatorcontrib>Estabrook, Joseph</creatorcontrib><creatorcontrib>Demir, Emek</creatorcontrib><creatorcontrib>Long, Nicola</creatorcontrib><creatorcontrib>Bottomly, Daniel</creatorcontrib><creatorcontrib>McWeeney, Shannon K</creatorcontrib><creatorcontrib>Tyner, Jeffrey W</creatorcontrib><creatorcontrib>Druker, Brian J</creatorcontrib><creatorcontrib>Maxson, Julia E</creatorcontrib><creatorcontrib>Braun, Theodore P</creatorcontrib><title>Disruption of the MYC Superenhancer Complex by Dual Targeting of FLT3 and LSD1 in Acute Myeloid Leukemia</title><title>Molecular cancer research</title><addtitle>Mol Cancer Res</addtitle><description>Mutations in Fms-like tyrosine kinase 3 (FLT3) are common drivers in acute myeloid leukemia (AML) yet FLT3 inhibitors only provide modest clinical benefit. Prior work has shown that inhibitors of lysine-specific demethylase 1 (LSD1) enhance kinase inhibitor activity in AML. Here we show that combined LSD1 and FLT3 inhibition induces synergistic cell death in FLT3-mutant AML. Multi-omic profiling revealed that the drug combination disrupts STAT5, LSD1, and GFI1 binding at the MYC blood superenhancer, suppressing superenhancer accessibility as well as MYC expression and activity. The drug combination simultaneously results in the accumulation of repressive H3K9me1 methylation, an LSD1 substrate, at MYC target genes. We validated these findings in 72 primary AML samples with the nearly every sample demonstrating synergistic responses to the drug combination. Collectively, these studies reveal how epigenetic therapies augment the activity of kinase inhibitors in FLT3-ITD (internal tandem duplication) AML.
This work establishes the synergistic efficacy of combined FLT3 and LSD1 inhibition in FLT3-ITD AML by disrupting STAT5 and GFI1 binding at the MYC blood-specific superenhancer complex.</description><subject>Apoptosis</subject><subject>fms-Like Tyrosine Kinase 3 - genetics</subject><subject>fms-Like Tyrosine Kinase 3 - metabolism</subject><subject>Histone Demethylases - genetics</subject><subject>Histone Demethylases - metabolism</subject><subject>Humans</subject><subject>Leukemia, Myeloid, Acute - drug therapy</subject><subject>Leukemia, Myeloid, Acute - genetics</subject><subject>Leukemia, Myeloid, Acute - metabolism</subject><subject>Mutation</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein Kinase Inhibitors - therapeutic use</subject><subject>STAT5 Transcription Factor - metabolism</subject><issn>1541-7786</issn><issn>1557-3125</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kMtOwzAURC0EouXxCSAv2aTEdvzIskopIAUhQVmwspzkmgbywk4k-vckamE1o6uZudJB6IqEC0K4uiU8IoGUSiyekpeA0iCUET9Cc8K5DBih_Hjyh8wMnXn_GYY0JFKcohkTsRSMsjnarkrvhq4v2wa3FvdbwE_vCX4dOnDQbE2Tg8NJW3cV_OBsh1eDqfDGuA_oy-ZjqqzTDcOmKXD6uiK4bPAyH_pxZQdVW45XGL6gLs0FOrGm8nB50HP0tr7bJA9B-nz_mCzTIGdc9IEVuY1BZZxEJiNhlqtCKgUWRGEKyUlsFJORIJGNiTQFt2rU3IjRsZBZys7RzX63c-33AL7XdelzqCrTQDt4TRVjIhKSx2OU76O5a713YHXnytq4nSahniDrCaCeAOoRsqZUT5DH3vXhxZDVUPy3_qiyX_hBd0M</recordid><startdate>20230705</startdate><enddate>20230705</enddate><creator>Yashar, William M</creator><creator>Curtiss, Brittany M</creator><creator>Coleman, Daniel J</creator><creator>VanCampen, Jake</creator><creator>Kong, Garth</creator><creator>Macaraeg, Jommel</creator><creator>Estabrook, Joseph</creator><creator>Demir, Emek</creator><creator>Long, Nicola</creator><creator>Bottomly, Daniel</creator><creator>McWeeney, Shannon K</creator><creator>Tyner, Jeffrey W</creator><creator>Druker, Brian J</creator><creator>Maxson, Julia E</creator><creator>Braun, Theodore P</creator><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><orcidid>https://orcid.org/0000-0001-8333-6607</orcidid><orcidid>https://orcid.org/0000-0003-1361-0927</orcidid><orcidid>https://orcid.org/0000-0001-8331-8206</orcidid><orcidid>https://orcid.org/0000-0002-6307-5056</orcidid><orcidid>https://orcid.org/0000-0002-8850-9850</orcidid><orcidid>https://orcid.org/0000-0002-5274-8323</orcidid><orcidid>https://orcid.org/0000-0002-3414-3160</orcidid><orcidid>https://orcid.org/0000-0002-3871-7221</orcidid><orcidid>https://orcid.org/0000-0002-2133-0960</orcidid><orcidid>https://orcid.org/0000-0002-3663-7113</orcidid><orcidid>https://orcid.org/0000-0002-6248-2143</orcidid><orcidid>https://orcid.org/0000-0002-9010-8167</orcidid><orcidid>https://orcid.org/0000-0002-1027-3315</orcidid><orcidid>https://orcid.org/0000-0001-7191-0990</orcidid><orcidid>https://orcid.org/0000-0001-5262-5406</orcidid></search><sort><creationdate>20230705</creationdate><title>Disruption of the MYC Superenhancer Complex by Dual Targeting of FLT3 and LSD1 in Acute Myeloid Leukemia</title><author>Yashar, William M ; Curtiss, Brittany M ; Coleman, Daniel J ; VanCampen, Jake ; Kong, Garth ; Macaraeg, Jommel ; Estabrook, Joseph ; Demir, Emek ; Long, Nicola ; Bottomly, Daniel ; McWeeney, Shannon K ; Tyner, Jeffrey W ; Druker, Brian J ; Maxson, Julia E ; Braun, Theodore P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-f6cf9e8b514ab10bc8d788efe6dad7519a8374614f917ad5f8917ca6d5f303f23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Apoptosis</topic><topic>fms-Like Tyrosine Kinase 3 - genetics</topic><topic>fms-Like Tyrosine Kinase 3 - metabolism</topic><topic>Histone Demethylases - genetics</topic><topic>Histone Demethylases - metabolism</topic><topic>Humans</topic><topic>Leukemia, Myeloid, Acute - drug therapy</topic><topic>Leukemia, Myeloid, Acute - genetics</topic><topic>Leukemia, Myeloid, Acute - metabolism</topic><topic>Mutation</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein Kinase Inhibitors - therapeutic use</topic><topic>STAT5 Transcription Factor - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yashar, William M</creatorcontrib><creatorcontrib>Curtiss, Brittany M</creatorcontrib><creatorcontrib>Coleman, Daniel J</creatorcontrib><creatorcontrib>VanCampen, Jake</creatorcontrib><creatorcontrib>Kong, Garth</creatorcontrib><creatorcontrib>Macaraeg, Jommel</creatorcontrib><creatorcontrib>Estabrook, Joseph</creatorcontrib><creatorcontrib>Demir, Emek</creatorcontrib><creatorcontrib>Long, Nicola</creatorcontrib><creatorcontrib>Bottomly, Daniel</creatorcontrib><creatorcontrib>McWeeney, Shannon K</creatorcontrib><creatorcontrib>Tyner, Jeffrey W</creatorcontrib><creatorcontrib>Druker, Brian J</creatorcontrib><creatorcontrib>Maxson, Julia E</creatorcontrib><creatorcontrib>Braun, Theodore P</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><jtitle>Molecular cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yashar, William M</au><au>Curtiss, Brittany M</au><au>Coleman, Daniel J</au><au>VanCampen, Jake</au><au>Kong, Garth</au><au>Macaraeg, Jommel</au><au>Estabrook, Joseph</au><au>Demir, Emek</au><au>Long, Nicola</au><au>Bottomly, Daniel</au><au>McWeeney, Shannon K</au><au>Tyner, Jeffrey W</au><au>Druker, Brian J</au><au>Maxson, Julia E</au><au>Braun, Theodore P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Disruption of the MYC Superenhancer Complex by Dual Targeting of FLT3 and LSD1 in Acute Myeloid Leukemia</atitle><jtitle>Molecular cancer research</jtitle><addtitle>Mol Cancer Res</addtitle><date>2023-07-05</date><risdate>2023</risdate><volume>21</volume><issue>7</issue><spage>631</spage><epage>647</epage><pages>631-647</pages><issn>1541-7786</issn><eissn>1557-3125</eissn><abstract>Mutations in Fms-like tyrosine kinase 3 (FLT3) are common drivers in acute myeloid leukemia (AML) yet FLT3 inhibitors only provide modest clinical benefit. Prior work has shown that inhibitors of lysine-specific demethylase 1 (LSD1) enhance kinase inhibitor activity in AML. Here we show that combined LSD1 and FLT3 inhibition induces synergistic cell death in FLT3-mutant AML. Multi-omic profiling revealed that the drug combination disrupts STAT5, LSD1, and GFI1 binding at the MYC blood superenhancer, suppressing superenhancer accessibility as well as MYC expression and activity. The drug combination simultaneously results in the accumulation of repressive H3K9me1 methylation, an LSD1 substrate, at MYC target genes. We validated these findings in 72 primary AML samples with the nearly every sample demonstrating synergistic responses to the drug combination. Collectively, these studies reveal how epigenetic therapies augment the activity of kinase inhibitors in FLT3-ITD (internal tandem duplication) AML.
This work establishes the synergistic efficacy of combined FLT3 and LSD1 inhibition in FLT3-ITD AML by disrupting STAT5 and GFI1 binding at the MYC blood-specific superenhancer complex.</abstract><cop>United States</cop><pmid>36976323</pmid><doi>10.1158/1541-7786.MCR-22-0745</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0001-8333-6607</orcidid><orcidid>https://orcid.org/0000-0003-1361-0927</orcidid><orcidid>https://orcid.org/0000-0001-8331-8206</orcidid><orcidid>https://orcid.org/0000-0002-6307-5056</orcidid><orcidid>https://orcid.org/0000-0002-8850-9850</orcidid><orcidid>https://orcid.org/0000-0002-5274-8323</orcidid><orcidid>https://orcid.org/0000-0002-3414-3160</orcidid><orcidid>https://orcid.org/0000-0002-3871-7221</orcidid><orcidid>https://orcid.org/0000-0002-2133-0960</orcidid><orcidid>https://orcid.org/0000-0002-3663-7113</orcidid><orcidid>https://orcid.org/0000-0002-6248-2143</orcidid><orcidid>https://orcid.org/0000-0002-9010-8167</orcidid><orcidid>https://orcid.org/0000-0002-1027-3315</orcidid><orcidid>https://orcid.org/0000-0001-7191-0990</orcidid><orcidid>https://orcid.org/0000-0001-5262-5406</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1541-7786 |
| ispartof | Molecular cancer research, 2023-07, Vol.21 (7), p.631-647 |
| issn | 1541-7786 1557-3125 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2833646759 |
| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals; Free Full-Text Journals in Chemistry |
| subjects | Apoptosis fms-Like Tyrosine Kinase 3 - genetics fms-Like Tyrosine Kinase 3 - metabolism Histone Demethylases - genetics Histone Demethylases - metabolism Humans Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - genetics Leukemia, Myeloid, Acute - metabolism Mutation Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - therapeutic use STAT5 Transcription Factor - metabolism |
| title | Disruption of the MYC Superenhancer Complex by Dual Targeting of FLT3 and LSD1 in Acute Myeloid Leukemia |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-27T16%3A39%3A36IST&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=Disruption%20of%20the%20MYC%20Superenhancer%20Complex%20by%20Dual%20Targeting%20of%20FLT3%20and%20LSD1%20in%20Acute%20Myeloid%20Leukemia&rft.jtitle=Molecular%20cancer%20research&rft.au=Yashar,%20William%20M&rft.date=2023-07-05&rft.volume=21&rft.issue=7&rft.spage=631&rft.epage=647&rft.pages=631-647&rft.issn=1541-7786&rft.eissn=1557-3125&rft_id=info:doi/10.1158/1541-7786.MCR-22-0745&rft_dat=%3Cproquest_cross%3E2833646759%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=2833646759&rft_id=info:pmid/36976323&rfr_iscdi=true |