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B-cell non-Hodgkin lymphoma: Selective vulnerability to PIKFYVE inhibition
We identified the PIKFYVE inhibitor apilimod as a potent and selective cytotoxic agent against B-cell non-Hodgkin lymphoma (B-NHL). Our data robustly establish PIKFYVE as the target through which apilimod kills B-NHL cells and show that apilimod-induced death in B-NHL is mediated by broad disruption...
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| Published in: | Autophagy 2017-06, Vol.13 (6), p.1082-1083 |
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| Main Authors: | , , , , , , , , , |
| Format: | Article |
| Language: | English |
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| container_end_page | 1083 |
| container_issue | 6 |
| container_start_page | 1082 |
| container_title | Autophagy |
| container_volume | 13 |
| creator | Gayle, Sophia Landrette, Sean Beeharry, Neil Conrad, Chris Hernandez, Marylens Beckett, Paul Ferguson, Shawn M. Xu, Tian Rothberg, Jonathan Lichenstein, Henri |
| description | We identified the PIKFYVE inhibitor apilimod as a potent and selective cytotoxic agent against B-cell non-Hodgkin lymphoma (B-NHL). Our data robustly establish PIKFYVE as the target through which apilimod kills B-NHL cells and show that apilimod-induced death in B-NHL is mediated by broad disruption of lysosome homeostasis characterized by lysosomal swelling, TFEB nuclear translocation, impaired maturation of lysosomal enzymes and incomplete autophagosome clearance. Furthermore, through genome-wide CRISPR knockout screening, we identified specific lysosomal genes (TFEB, CLCN7, OSTM1 and SNX10) as critical determinants of apilimod-induced cytotoxicity. Together these data highlight disruption of lysosome homeostasis through PIKFYVE inhibition as a novel anticancer mechanism in B-NHL and potentially other cancers. |
| doi_str_mv | 10.1080/15548627.2017.1304871 |
| format | article |
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Our data robustly establish PIKFYVE as the target through which apilimod kills B-NHL cells and show that apilimod-induced death in B-NHL is mediated by broad disruption of lysosome homeostasis characterized by lysosomal swelling, TFEB nuclear translocation, impaired maturation of lysosomal enzymes and incomplete autophagosome clearance. Furthermore, through genome-wide CRISPR knockout screening, we identified specific lysosomal genes (TFEB, CLCN7, OSTM1 and SNX10) as critical determinants of apilimod-induced cytotoxicity. Together these data highlight disruption of lysosome homeostasis through PIKFYVE inhibition as a novel anticancer mechanism in B-NHL and potentially other cancers.</description><identifier>ISSN: 1554-8627</identifier><identifier>EISSN: 1554-8635</identifier><identifier>DOI: 10.1080/15548627.2017.1304871</identifier><identifier>PMID: 28350209</identifier><language>eng</language><publisher>United States: Taylor & Francis</publisher><subject>apilimod ; Autophagic Punctum ; autophagy ; B-Lymphocytes - drug effects ; B-Lymphocytes - enzymology ; B-Lymphocytes - pathology ; CLCN7 ; Endosomes - metabolism ; Humans ; lymphoma ; Lymphoma, Non-Hodgkin - drug therapy ; Lymphoma, Non-Hodgkin - enzymology ; Lymphoma, Non-Hodgkin - pathology ; Lysosomes - metabolism ; Models, Biological ; Phosphatidylinositol 3-Kinases - antagonists & inhibitors ; Phosphatidylinositol 3-Kinases - metabolism ; PIKFYVE ; Protein Kinase Inhibitors - pharmacology ; Protein Kinase Inhibitors - therapeutic use ; TFEB</subject><ispartof>Autophagy, 2017-06, Vol.13 (6), p.1082-1083</ispartof><rights>2017 Taylor & Francis 2017</rights><rights>2017 Taylor & Francis 2017 Taylor & Francis</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c468t-a729f83c0a984f00d149dca1c0187078d131c22f53822e68361205aab8fdcfad3</citedby><orcidid>0000-0002-9495-8388</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486370/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486370/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28350209$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gayle, Sophia</creatorcontrib><creatorcontrib>Landrette, Sean</creatorcontrib><creatorcontrib>Beeharry, Neil</creatorcontrib><creatorcontrib>Conrad, Chris</creatorcontrib><creatorcontrib>Hernandez, Marylens</creatorcontrib><creatorcontrib>Beckett, Paul</creatorcontrib><creatorcontrib>Ferguson, Shawn M.</creatorcontrib><creatorcontrib>Xu, Tian</creatorcontrib><creatorcontrib>Rothberg, Jonathan</creatorcontrib><creatorcontrib>Lichenstein, Henri</creatorcontrib><title>B-cell non-Hodgkin lymphoma: Selective vulnerability to PIKFYVE inhibition</title><title>Autophagy</title><addtitle>Autophagy</addtitle><description>We identified the PIKFYVE inhibitor apilimod as a potent and selective cytotoxic agent against B-cell non-Hodgkin lymphoma (B-NHL). Our data robustly establish PIKFYVE as the target through which apilimod kills B-NHL cells and show that apilimod-induced death in B-NHL is mediated by broad disruption of lysosome homeostasis characterized by lysosomal swelling, TFEB nuclear translocation, impaired maturation of lysosomal enzymes and incomplete autophagosome clearance. Furthermore, through genome-wide CRISPR knockout screening, we identified specific lysosomal genes (TFEB, CLCN7, OSTM1 and SNX10) as critical determinants of apilimod-induced cytotoxicity. Together these data highlight disruption of lysosome homeostasis through PIKFYVE inhibition as a novel anticancer mechanism in B-NHL and potentially other cancers.</description><subject>apilimod</subject><subject>Autophagic Punctum</subject><subject>autophagy</subject><subject>B-Lymphocytes - drug effects</subject><subject>B-Lymphocytes - enzymology</subject><subject>B-Lymphocytes - pathology</subject><subject>CLCN7</subject><subject>Endosomes - metabolism</subject><subject>Humans</subject><subject>lymphoma</subject><subject>Lymphoma, Non-Hodgkin - drug therapy</subject><subject>Lymphoma, Non-Hodgkin - enzymology</subject><subject>Lymphoma, Non-Hodgkin - pathology</subject><subject>Lysosomes - metabolism</subject><subject>Models, Biological</subject><subject>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>PIKFYVE</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein Kinase Inhibitors - therapeutic use</subject><subject>TFEB</subject><issn>1554-8627</issn><issn>1554-8635</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><recordid>eNp9UctOIzEQtBCI9yfsao5cJrTtmbGHw2oB8UYCiYfEyXI8NjHrsYM9Ccrfk1FCtFw4dau7uqpVhdAvDAMMHA5xWRa8ImxAALMBplBwhtfQdj_PeUXL9VVP2BbaSekNgFa8Jptoi3BaAoF6G12f5Eo7l_ng88vQvP6zPnOzdjwKrTzKHrTTqrNTnU0nzusoh9bZbpZ1Ibu_ujl_eT7LrB_Zoe1s8Htow0iX9P6y7qKn87PH08v89u7i6vT4NldFxbtcMlIbThXImhcGoMFF3SiJFWDOgPEGU6wIMSXlhOiK0woTKKUcctMoIxu6i_4seMeTYasbpX0XpRPjaFsZZyJIK75vvB2J1zAVvWGUwZzgYEkQw_tEp060NvUuSK_DJAnMOWaMUIrn0HIBVTGkFLVZyWAQfQ7iKwfR5yCWOczvfv__4-rqy_g54O8CYL0JsZUfIbpGdHLmQjRRemWToD9rfALD5Zek</recordid><startdate>20170603</startdate><enddate>20170603</enddate><creator>Gayle, Sophia</creator><creator>Landrette, Sean</creator><creator>Beeharry, Neil</creator><creator>Conrad, Chris</creator><creator>Hernandez, Marylens</creator><creator>Beckett, Paul</creator><creator>Ferguson, Shawn M.</creator><creator>Xu, Tian</creator><creator>Rothberg, Jonathan</creator><creator>Lichenstein, Henri</creator><general>Taylor & Francis</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>5PM</scope><orcidid>https://orcid.org/0000-0002-9495-8388</orcidid></search><sort><creationdate>20170603</creationdate><title>B-cell non-Hodgkin lymphoma: Selective vulnerability to PIKFYVE inhibition</title><author>Gayle, Sophia ; Landrette, Sean ; Beeharry, Neil ; Conrad, Chris ; Hernandez, Marylens ; Beckett, Paul ; Ferguson, Shawn M. ; Xu, Tian ; Rothberg, Jonathan ; Lichenstein, Henri</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c468t-a729f83c0a984f00d149dca1c0187078d131c22f53822e68361205aab8fdcfad3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>apilimod</topic><topic>Autophagic Punctum</topic><topic>autophagy</topic><topic>B-Lymphocytes - drug effects</topic><topic>B-Lymphocytes - enzymology</topic><topic>B-Lymphocytes - pathology</topic><topic>CLCN7</topic><topic>Endosomes - metabolism</topic><topic>Humans</topic><topic>lymphoma</topic><topic>Lymphoma, Non-Hodgkin - drug therapy</topic><topic>Lymphoma, Non-Hodgkin - enzymology</topic><topic>Lymphoma, Non-Hodgkin - pathology</topic><topic>Lysosomes - metabolism</topic><topic>Models, Biological</topic><topic>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>PIKFYVE</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein Kinase Inhibitors - therapeutic use</topic><topic>TFEB</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gayle, Sophia</creatorcontrib><creatorcontrib>Landrette, Sean</creatorcontrib><creatorcontrib>Beeharry, Neil</creatorcontrib><creatorcontrib>Conrad, Chris</creatorcontrib><creatorcontrib>Hernandez, Marylens</creatorcontrib><creatorcontrib>Beckett, Paul</creatorcontrib><creatorcontrib>Ferguson, Shawn M.</creatorcontrib><creatorcontrib>Xu, Tian</creatorcontrib><creatorcontrib>Rothberg, Jonathan</creatorcontrib><creatorcontrib>Lichenstein, Henri</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>PubMed Central (Full Participant titles)</collection><jtitle>Autophagy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gayle, Sophia</au><au>Landrette, Sean</au><au>Beeharry, Neil</au><au>Conrad, Chris</au><au>Hernandez, Marylens</au><au>Beckett, Paul</au><au>Ferguson, Shawn M.</au><au>Xu, Tian</au><au>Rothberg, Jonathan</au><au>Lichenstein, Henri</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>B-cell non-Hodgkin lymphoma: Selective vulnerability to PIKFYVE inhibition</atitle><jtitle>Autophagy</jtitle><addtitle>Autophagy</addtitle><date>2017-06-03</date><risdate>2017</risdate><volume>13</volume><issue>6</issue><spage>1082</spage><epage>1083</epage><pages>1082-1083</pages><issn>1554-8627</issn><eissn>1554-8635</eissn><abstract>We identified the PIKFYVE inhibitor apilimod as a potent and selective cytotoxic agent against B-cell non-Hodgkin lymphoma (B-NHL). Our data robustly establish PIKFYVE as the target through which apilimod kills B-NHL cells and show that apilimod-induced death in B-NHL is mediated by broad disruption of lysosome homeostasis characterized by lysosomal swelling, TFEB nuclear translocation, impaired maturation of lysosomal enzymes and incomplete autophagosome clearance. Furthermore, through genome-wide CRISPR knockout screening, we identified specific lysosomal genes (TFEB, CLCN7, OSTM1 and SNX10) as critical determinants of apilimod-induced cytotoxicity. Together these data highlight disruption of lysosome homeostasis through PIKFYVE inhibition as a novel anticancer mechanism in B-NHL and potentially other cancers.</abstract><cop>United States</cop><pub>Taylor & Francis</pub><pmid>28350209</pmid><doi>10.1080/15548627.2017.1304871</doi><tpages>2</tpages><orcidid>https://orcid.org/0000-0002-9495-8388</orcidid><oa>free_for_read</oa></addata></record> |
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| language | eng |
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| source | PubMed Central (Open Access); Taylor and Francis Science and Technology Collection |
| subjects | apilimod Autophagic Punctum autophagy B-Lymphocytes - drug effects B-Lymphocytes - enzymology B-Lymphocytes - pathology CLCN7 Endosomes - metabolism Humans lymphoma Lymphoma, Non-Hodgkin - drug therapy Lymphoma, Non-Hodgkin - enzymology Lymphoma, Non-Hodgkin - pathology Lysosomes - metabolism Models, Biological Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphatidylinositol 3-Kinases - metabolism PIKFYVE Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - therapeutic use TFEB |
| title | B-cell non-Hodgkin lymphoma: Selective vulnerability to PIKFYVE inhibition |
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