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ULK1 inhibition as a targeted therapeutic strategy for FLT3-ITD-mutated acute myeloid leukemia
In acute myeloid leukemia (AML), internal tandem duplication mutations in the FLT3 tyrosine kinase receptor (FLT3-ITD) are associated with a dismal outcome. Although uncoordinated 51-like kinase 1 (ULK1), which plays a central role in the autophagy pathway, has emerged as a novel therapeutic target...
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Published in: | Journal of experimental & clinical cancer research 2020-05, Vol.39 (1), p.85-85, Article 85 |
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description | In acute myeloid leukemia (AML), internal tandem duplication mutations in the FLT3 tyrosine kinase receptor (FLT3-ITD) are associated with a dismal outcome. Although uncoordinated 51-like kinase 1 (ULK1), which plays a central role in the autophagy pathway, has emerged as a novel therapeutic target for various cancers, its role in FLT3-ITD AML remains elusive. In this study, we evaluated the effects of ULK1 inhibition on leukemia cell death in FLT3-ITD AML.
We evaluated ULK1 expression and the levels of apoptosis and autophagy following ULK1 inhibition in FLT3-ITD AML cell lines and investigated the mechanism underlying apoptosis induced by ULK1 inhibition. Statistical analysis was performed using GraphPad Prism 4.0 (GraphPad Software Inc).
FLT3-ITD AML cells showed significantly higher ULK1 expression than FLT3-wild-type (WT) AML cells. Two ULK1 inhibitors, MRT 68921 and SBI-0206965, induced apoptosis in FLT3-ITD AML cells, with relatively minimal effects on FLT3-WT AML cells and normal CD34-positive cells. Apoptosis induction by ULK1 inhibition was associated with caspase pathway activation. Interestingly, ULK1 inhibition paradoxically also induced autophagy, showing synergistic interaction with autophagy inhibitors. Hence, autophagy may act as a prosurvival mechanism in FLT3-ITD AML cells. FLT3-ITD protein degradation and inhibition of the ERK, AKT, and STAT5 pathways were also observed in FLT3-ITD AML cells following treatment with ULK1 inhibitors.
ULK1 is a viable drug target and ULK1 inhibition may represent a promising therapeutic strategy against FLT3-ITD AML. |
doi_str_mv | 10.1186/s13046-020-01580-4 |
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We evaluated ULK1 expression and the levels of apoptosis and autophagy following ULK1 inhibition in FLT3-ITD AML cell lines and investigated the mechanism underlying apoptosis induced by ULK1 inhibition. Statistical analysis was performed using GraphPad Prism 4.0 (GraphPad Software Inc).
FLT3-ITD AML cells showed significantly higher ULK1 expression than FLT3-wild-type (WT) AML cells. Two ULK1 inhibitors, MRT 68921 and SBI-0206965, induced apoptosis in FLT3-ITD AML cells, with relatively minimal effects on FLT3-WT AML cells and normal CD34-positive cells. Apoptosis induction by ULK1 inhibition was associated with caspase pathway activation. Interestingly, ULK1 inhibition paradoxically also induced autophagy, showing synergistic interaction with autophagy inhibitors. Hence, autophagy may act as a prosurvival mechanism in FLT3-ITD AML cells. FLT3-ITD protein degradation and inhibition of the ERK, AKT, and STAT5 pathways were also observed in FLT3-ITD AML cells following treatment with ULK1 inhibitors.
ULK1 is a viable drug target and ULK1 inhibition may represent a promising therapeutic strategy against FLT3-ITD AML.</description><identifier>ISSN: 1756-9966</identifier><identifier>ISSN: 0392-9078</identifier><identifier>EISSN: 1756-9966</identifier><identifier>DOI: 10.1186/s13046-020-01580-4</identifier><identifier>PMID: 32393312</identifier><language>eng</language><publisher>England: BioMed Central Ltd</publisher><subject>Acute myelocytic leukemia ; Acute myeloid leukemia ; Analysis ; Apoptosis ; Apoptosis - drug effects ; Autophagy ; Autophagy - drug effects ; Autophagy-Related Protein-1 Homolog - antagonists & inhibitors ; Autophagy-Related Protein-1 Homolog - biosynthesis ; Autophagy-Related Protein-1 Homolog - metabolism ; Benzamides - pharmacology ; Cancer research ; Cancer therapies ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Chemotherapy ; Development and progression ; FLT3-ITD mutation ; fms-Like Tyrosine Kinase 3 - genetics ; fms-Like Tyrosine Kinase 3 - metabolism ; Genetic aspects ; Health aspects ; Humans ; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors ; Intracellular Signaling Peptides and Proteins - biosynthesis ; Intracellular Signaling Peptides and Proteins - metabolism ; Kinases ; Leukemia ; Leukemia, Myeloid, Acute - drug therapy ; Leukemia, Myeloid, Acute - genetics ; Leukemia, Myeloid, Acute - metabolism ; Leukemia, Myeloid, Acute - pathology ; Medical prognosis ; Midostaurin ; Molecular Targeted Therapy ; Mutation ; Patients ; Protein Kinase Inhibitors - pharmacology ; Proteins ; Proteolysis ; Pyrimidines - pharmacology ; Software industry ; Stem cells ; Transfection ; Tumors ; Tyrosine ; ULK1</subject><ispartof>Journal of experimental & clinical cancer research, 2020-05, Vol.39 (1), p.85-85, Article 85</ispartof><rights>COPYRIGHT 2020 BioMed Central Ltd.</rights><rights>2020. This work is licensed under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>The Author(s) 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c660t-6d3059a4c41abb0299c26a53c9457a7792818b3910e8d7cda372813c7a8c2cf23</citedby><cites>FETCH-LOGICAL-c660t-6d3059a4c41abb0299c26a53c9457a7792818b3910e8d7cda372813c7a8c2cf23</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/PMC7212592/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2404280821?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,37013,44590,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32393312$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hwang, Doh Yu</creatorcontrib><creatorcontrib>Eom, Ju-In</creatorcontrib><creatorcontrib>Jang, Ji Eun</creatorcontrib><creatorcontrib>Jeung, Hoi-Kyung</creatorcontrib><creatorcontrib>Chung, Haerim</creatorcontrib><creatorcontrib>Kim, Jin Seok</creatorcontrib><creatorcontrib>Cheong, June-Won</creatorcontrib><creatorcontrib>Min, Yoo Hong</creatorcontrib><title>ULK1 inhibition as a targeted therapeutic strategy for FLT3-ITD-mutated acute myeloid leukemia</title><title>Journal of experimental & clinical cancer research</title><addtitle>J Exp Clin Cancer Res</addtitle><description>In acute myeloid leukemia (AML), internal tandem duplication mutations in the FLT3 tyrosine kinase receptor (FLT3-ITD) are associated with a dismal outcome. Although uncoordinated 51-like kinase 1 (ULK1), which plays a central role in the autophagy pathway, has emerged as a novel therapeutic target for various cancers, its role in FLT3-ITD AML remains elusive. In this study, we evaluated the effects of ULK1 inhibition on leukemia cell death in FLT3-ITD AML.
We evaluated ULK1 expression and the levels of apoptosis and autophagy following ULK1 inhibition in FLT3-ITD AML cell lines and investigated the mechanism underlying apoptosis induced by ULK1 inhibition. Statistical analysis was performed using GraphPad Prism 4.0 (GraphPad Software Inc).
FLT3-ITD AML cells showed significantly higher ULK1 expression than FLT3-wild-type (WT) AML cells. Two ULK1 inhibitors, MRT 68921 and SBI-0206965, induced apoptosis in FLT3-ITD AML cells, with relatively minimal effects on FLT3-WT AML cells and normal CD34-positive cells. Apoptosis induction by ULK1 inhibition was associated with caspase pathway activation. Interestingly, ULK1 inhibition paradoxically also induced autophagy, showing synergistic interaction with autophagy inhibitors. Hence, autophagy may act as a prosurvival mechanism in FLT3-ITD AML cells. FLT3-ITD protein degradation and inhibition of the ERK, AKT, and STAT5 pathways were also observed in FLT3-ITD AML cells following treatment with ULK1 inhibitors.
ULK1 is a viable drug target and ULK1 inhibition may represent a promising therapeutic strategy against FLT3-ITD AML.</description><subject>Acute myelocytic leukemia</subject><subject>Acute myeloid leukemia</subject><subject>Analysis</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Autophagy</subject><subject>Autophagy - drug effects</subject><subject>Autophagy-Related Protein-1 Homolog - antagonists & inhibitors</subject><subject>Autophagy-Related Protein-1 Homolog - biosynthesis</subject><subject>Autophagy-Related Protein-1 Homolog - metabolism</subject><subject>Benzamides - pharmacology</subject><subject>Cancer research</subject><subject>Cancer therapies</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Chemotherapy</subject><subject>Development and progression</subject><subject>FLT3-ITD mutation</subject><subject>fms-Like Tyrosine Kinase 3 - genetics</subject><subject>fms-Like Tyrosine Kinase 3 - metabolism</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Intracellular Signaling Peptides and Proteins - antagonists & inhibitors</subject><subject>Intracellular Signaling Peptides and Proteins - biosynthesis</subject><subject>Intracellular Signaling Peptides and Proteins - metabolism</subject><subject>Kinases</subject><subject>Leukemia</subject><subject>Leukemia, Myeloid, Acute - drug therapy</subject><subject>Leukemia, Myeloid, Acute - genetics</subject><subject>Leukemia, Myeloid, Acute - metabolism</subject><subject>Leukemia, Myeloid, Acute - pathology</subject><subject>Medical prognosis</subject><subject>Midostaurin</subject><subject>Molecular Targeted Therapy</subject><subject>Mutation</subject><subject>Patients</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Proteins</subject><subject>Proteolysis</subject><subject>Pyrimidines - pharmacology</subject><subject>Software industry</subject><subject>Stem cells</subject><subject>Transfection</subject><subject>Tumors</subject><subject>Tyrosine</subject><subject>ULK1</subject><issn>1756-9966</issn><issn>0392-9078</issn><issn>1756-9966</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNptkl9v0zAUxSMEYmPwBXhAkZAmXjL8P_YL0jQYVFTipXvFunGc1iWJi-0g9dvjrGO0COXB0fXvHvtcn6J4jdEVxlK8j5giJipEUIUwl6hiT4pzXHNRKSXE06P_s-JFjFuEBFZYPS_OKKGKUkzOi-93y6-4dOPGNS45P5YQSygThLVNti3TxgbY2Sk5U8YUINn1vux8KG-XK1otVh-rYUowk2CmZMthb3vv2rK30w87OHhZPOugj_bVw3pR3N1-Wt18qZbfPi9urpeVEQKlSrQUcQXMMAxNg4hShgjg1CjGa6hrRSSWDVUYWdnWpgVa5wo1NUhDTEfoRbE46LYetnoX3ABhrz04fV_wYa0hZBO91UpyjISCrmkUs5RKg1XLOGUAnCNTZ60PB63d1Ay2NXbMxvsT0dOd0W302v_SNcGEq_ky7x4Egv852Zj04KKxfQ-j9VPUhCEsMceMZfTtP-jWT2HMo5opRiSSBP-l1pANuLHz-Vwzi-prQWrGGJY8U1f_ofLX5pcwfrSdy_WThsujho2FPm2i76c5B_EUJAfQBB9jsN3jMDDScxT1IYo6R1HfR1HP1t4cj_Gx5U_26G8xgtWs</recordid><startdate>20200511</startdate><enddate>20200511</enddate><creator>Hwang, Doh Yu</creator><creator>Eom, Ju-In</creator><creator>Jang, Ji Eun</creator><creator>Jeung, Hoi-Kyung</creator><creator>Chung, Haerim</creator><creator>Kim, Jin Seok</creator><creator>Cheong, June-Won</creator><creator>Min, Yoo Hong</creator><general>BioMed Central Ltd</general><general>BioMed Central</general><general>BMC</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>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20200511</creationdate><title>ULK1 inhibition as a targeted therapeutic strategy for FLT3-ITD-mutated acute myeloid leukemia</title><author>Hwang, Doh Yu ; Eom, Ju-In ; Jang, Ji Eun ; Jeung, Hoi-Kyung ; Chung, Haerim ; Kim, Jin Seok ; Cheong, June-Won ; Min, Yoo Hong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c660t-6d3059a4c41abb0299c26a53c9457a7792818b3910e8d7cda372813c7a8c2cf23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Acute myelocytic leukemia</topic><topic>Acute myeloid leukemia</topic><topic>Analysis</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Autophagy</topic><topic>Autophagy - drug effects</topic><topic>Autophagy-Related Protein-1 Homolog - antagonists & inhibitors</topic><topic>Autophagy-Related Protein-1 Homolog - biosynthesis</topic><topic>Autophagy-Related Protein-1 Homolog - metabolism</topic><topic>Benzamides - pharmacology</topic><topic>Cancer research</topic><topic>Cancer therapies</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Chemotherapy</topic><topic>Development and progression</topic><topic>FLT3-ITD mutation</topic><topic>fms-Like Tyrosine Kinase 3 - genetics</topic><topic>fms-Like Tyrosine Kinase 3 - metabolism</topic><topic>Genetic aspects</topic><topic>Health aspects</topic><topic>Humans</topic><topic>Intracellular Signaling Peptides and Proteins - antagonists & inhibitors</topic><topic>Intracellular Signaling Peptides and Proteins - biosynthesis</topic><topic>Intracellular Signaling Peptides and Proteins - metabolism</topic><topic>Kinases</topic><topic>Leukemia</topic><topic>Leukemia, Myeloid, Acute - drug therapy</topic><topic>Leukemia, Myeloid, Acute - genetics</topic><topic>Leukemia, Myeloid, Acute - metabolism</topic><topic>Leukemia, Myeloid, Acute - pathology</topic><topic>Medical prognosis</topic><topic>Midostaurin</topic><topic>Molecular Targeted Therapy</topic><topic>Mutation</topic><topic>Patients</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Proteins</topic><topic>Proteolysis</topic><topic>Pyrimidines - pharmacology</topic><topic>Software industry</topic><topic>Stem cells</topic><topic>Transfection</topic><topic>Tumors</topic><topic>Tyrosine</topic><topic>ULK1</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hwang, Doh Yu</creatorcontrib><creatorcontrib>Eom, Ju-In</creatorcontrib><creatorcontrib>Jang, Ji Eun</creatorcontrib><creatorcontrib>Jeung, Hoi-Kyung</creatorcontrib><creatorcontrib>Chung, Haerim</creatorcontrib><creatorcontrib>Kim, Jin Seok</creatorcontrib><creatorcontrib>Cheong, June-Won</creatorcontrib><creatorcontrib>Min, Yoo Hong</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>ProQuest_Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</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)</collection><collection>ProQuest Central</collection><collection>ProQuest Central</collection><collection>AUTh Library subscriptions: ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Publicly Available Content Database (Proquest) (PQ_SDU_P3)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>Directory of Open Access Journals</collection><jtitle>Journal of experimental & clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hwang, Doh Yu</au><au>Eom, Ju-In</au><au>Jang, Ji Eun</au><au>Jeung, Hoi-Kyung</au><au>Chung, Haerim</au><au>Kim, Jin Seok</au><au>Cheong, June-Won</au><au>Min, Yoo Hong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>ULK1 inhibition as a targeted therapeutic strategy for FLT3-ITD-mutated acute myeloid leukemia</atitle><jtitle>Journal of experimental & clinical cancer research</jtitle><addtitle>J Exp Clin Cancer Res</addtitle><date>2020-05-11</date><risdate>2020</risdate><volume>39</volume><issue>1</issue><spage>85</spage><epage>85</epage><pages>85-85</pages><artnum>85</artnum><issn>1756-9966</issn><issn>0392-9078</issn><eissn>1756-9966</eissn><abstract>In acute myeloid leukemia (AML), internal tandem duplication mutations in the FLT3 tyrosine kinase receptor (FLT3-ITD) are associated with a dismal outcome. Although uncoordinated 51-like kinase 1 (ULK1), which plays a central role in the autophagy pathway, has emerged as a novel therapeutic target for various cancers, its role in FLT3-ITD AML remains elusive. In this study, we evaluated the effects of ULK1 inhibition on leukemia cell death in FLT3-ITD AML.
We evaluated ULK1 expression and the levels of apoptosis and autophagy following ULK1 inhibition in FLT3-ITD AML cell lines and investigated the mechanism underlying apoptosis induced by ULK1 inhibition. Statistical analysis was performed using GraphPad Prism 4.0 (GraphPad Software Inc).
FLT3-ITD AML cells showed significantly higher ULK1 expression than FLT3-wild-type (WT) AML cells. Two ULK1 inhibitors, MRT 68921 and SBI-0206965, induced apoptosis in FLT3-ITD AML cells, with relatively minimal effects on FLT3-WT AML cells and normal CD34-positive cells. Apoptosis induction by ULK1 inhibition was associated with caspase pathway activation. Interestingly, ULK1 inhibition paradoxically also induced autophagy, showing synergistic interaction with autophagy inhibitors. Hence, autophagy may act as a prosurvival mechanism in FLT3-ITD AML cells. FLT3-ITD protein degradation and inhibition of the ERK, AKT, and STAT5 pathways were also observed in FLT3-ITD AML cells following treatment with ULK1 inhibitors.
ULK1 is a viable drug target and ULK1 inhibition may represent a promising therapeutic strategy against FLT3-ITD AML.</abstract><cop>England</cop><pub>BioMed Central Ltd</pub><pmid>32393312</pmid><doi>10.1186/s13046-020-01580-4</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Acute myelocytic leukemia Acute myeloid leukemia Analysis Apoptosis Apoptosis - drug effects Autophagy Autophagy - drug effects Autophagy-Related Protein-1 Homolog - antagonists & inhibitors Autophagy-Related Protein-1 Homolog - biosynthesis Autophagy-Related Protein-1 Homolog - metabolism Benzamides - pharmacology Cancer research Cancer therapies Cell Line, Tumor Cell Proliferation - drug effects Chemotherapy Development and progression FLT3-ITD mutation fms-Like Tyrosine Kinase 3 - genetics fms-Like Tyrosine Kinase 3 - metabolism Genetic aspects Health aspects Humans Intracellular Signaling Peptides and Proteins - antagonists & inhibitors Intracellular Signaling Peptides and Proteins - biosynthesis Intracellular Signaling Peptides and Proteins - metabolism Kinases Leukemia Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - genetics Leukemia, Myeloid, Acute - metabolism Leukemia, Myeloid, Acute - pathology Medical prognosis Midostaurin Molecular Targeted Therapy Mutation Patients Protein Kinase Inhibitors - pharmacology Proteins Proteolysis Pyrimidines - pharmacology Software industry Stem cells Transfection Tumors Tyrosine ULK1 |
title | ULK1 inhibition as a targeted therapeutic strategy for FLT3-ITD-mutated acute myeloid leukemia |
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