ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia
Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are common in acute myeloid leukemia (AML) and drive leukemic cell growth and survival. Although FLT3 inhibitors have shown considerable promise for the treatment of AML, they ultimately fail to achieve long-term remissions as monotherapy. To...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2016-10, Vol.113 (43), p.E6669-E6678 |
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| creator | Gregory, Mark A. D’Alessandro, Angelo Alvarez-Calderon, Francesca Kim, Jihye Nemkov, Travis Adane, Biniam Rozhok, Andrii I. Kumar, Amit Kumar, Vijay Pollyea, Daniel A. Wempe, Michael F. Jordan, Craig T. Serkova, Natalie J. Choon Tan, Aik Hansen, Kirk C. DeGregori, James |
| description | Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are common in acute myeloid leukemia (AML) and drive leukemic cell growth and survival. Although FLT3 inhibitors have shown considerable promise for the treatment of AML, they ultimately fail to achieve long-term remissions as monotherapy. To identify genetic targets that can sensitize AML cells to killing by FLT3 inhibitors, we performed a genome-wide RNA interference (RNAi)-based screen that identified ATM (ataxia telangiectasia mutated) as being synthetic lethal with FLT3 inhibitor therapy. We found that inactivating ATM or its downstream effector glucose 6-phosphate dehydrogenase (G6PD) sensitizes AML cells to FLT3 inhibitor induced apoptosis. Examination of the cellular metabolome showed that FLT3 inhibition by itself causes profound alterations in central carbon metabolism, resulting in impaired production of the antioxidant factor glutathione, which was further impaired by ATM or G6PD inactivation. Moreover, FLT3 inhibition elicited severe mitochondrial oxidative stress that is causative in apoptosis and is exacerbated by ATM/G6PD inhibition. The use of an agent that intensifies mitochondrial oxidative stress in combination with a FLT3 inhibitor augmented elimination of AML cells in vitro and in vivo, revealing a therapeutic strategy for the improved treatment of FLT3 mutated AML. |
| doi_str_mv | 10.1073/pnas.1603876113 |
| format | Article |
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Although FLT3 inhibitors have shown considerable promise for the treatment of AML, they ultimately fail to achieve long-term remissions as monotherapy. To identify genetic targets that can sensitize AML cells to killing by FLT3 inhibitors, we performed a genome-wide RNA interference (RNAi)-based screen that identified ATM (ataxia telangiectasia mutated) as being synthetic lethal with FLT3 inhibitor therapy. We found that inactivating ATM or its downstream effector glucose 6-phosphate dehydrogenase (G6PD) sensitizes AML cells to FLT3 inhibitor induced apoptosis. Examination of the cellular metabolome showed that FLT3 inhibition by itself causes profound alterations in central carbon metabolism, resulting in impaired production of the antioxidant factor glutathione, which was further impaired by ATM or G6PD inactivation. Moreover, FLT3 inhibition elicited severe mitochondrial oxidative stress that is causative in apoptosis and is exacerbated by ATM/G6PD inhibition. The use of an agent that intensifies mitochondrial oxidative stress in combination with a FLT3 inhibitor augmented elimination of AML cells in vitro and in vivo, revealing a therapeutic strategy for the improved treatment of FLT3 mutated AML.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1603876113</identifier><identifier>PMID: 27791036</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; Antineoplastic Agents - pharmacology ; Ataxia Telangiectasia Mutated Proteins - antagonists & inhibitors ; Ataxia Telangiectasia Mutated Proteins - genetics ; Ataxia Telangiectasia Mutated Proteins - metabolism ; Benzothiazoles - pharmacology ; Biological Sciences ; Cell growth ; Cell Line, Tumor ; Cell Survival - drug effects ; Drug Resistance, Neoplasm - genetics ; Drug Therapy, Combination ; Female ; fms-Like Tyrosine Kinase 3 - antagonists & inhibitors ; fms-Like Tyrosine Kinase 3 - genetics ; fms-Like Tyrosine Kinase 3 - metabolism ; Gene Expression Regulation, Leukemic ; Genetics ; Glucosephosphate Dehydrogenase - antagonists & inhibitors ; Glucosephosphate Dehydrogenase - genetics ; Glucosephosphate Dehydrogenase - metabolism ; Humans ; Hydrazines - pharmacology ; Kinases ; Leukemia ; Leukemia, Myeloid, Acute - drug therapy ; Leukemia, Myeloid, Acute - genetics ; Leukemia, Myeloid, Acute - mortality ; Leukemia, Myeloid, Acute - pathology ; Metabolism ; Mice, Inbred NOD ; Middle Aged ; Mutation ; Oxidation-Reduction ; Phenylurea Compounds - pharmacology ; PNAS Plus ; Protein Kinase Inhibitors - pharmacology ; RNA, Small Interfering - genetics ; RNA, Small Interfering - metabolism ; Signal Transduction ; Survival Analysis ; Xenograft Model Antitumor Assays</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2016-10, Vol.113 (43), p.E6669-E6678</ispartof><rights>Volumes 1–89 and 106–113, copyright as a collective work only; author(s) retains copyright to individual articles</rights><rights>Copyright National Academy of Sciences Oct 25, 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c476t-d1e1f6e406ce3e4daa0b036a25f5778f2312e154d34557e1cb59ce5012d5fecc3</citedby><cites>FETCH-LOGICAL-c476t-d1e1f6e406ce3e4daa0b036a25f5778f2312e154d34557e1cb59ce5012d5fecc3</cites><orcidid>0000-0001-5587-4686</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26472264$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26472264$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27924,27925,53791,53793,58017,58250</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27791036$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gregory, Mark A.</creatorcontrib><creatorcontrib>D’Alessandro, Angelo</creatorcontrib><creatorcontrib>Alvarez-Calderon, Francesca</creatorcontrib><creatorcontrib>Kim, Jihye</creatorcontrib><creatorcontrib>Nemkov, Travis</creatorcontrib><creatorcontrib>Adane, Biniam</creatorcontrib><creatorcontrib>Rozhok, Andrii I.</creatorcontrib><creatorcontrib>Kumar, Amit</creatorcontrib><creatorcontrib>Kumar, Vijay</creatorcontrib><creatorcontrib>Pollyea, Daniel A.</creatorcontrib><creatorcontrib>Wempe, Michael F.</creatorcontrib><creatorcontrib>Jordan, Craig T.</creatorcontrib><creatorcontrib>Serkova, Natalie J.</creatorcontrib><creatorcontrib>Choon Tan, Aik</creatorcontrib><creatorcontrib>Hansen, Kirk C.</creatorcontrib><creatorcontrib>DeGregori, James</creatorcontrib><title>ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are common in acute myeloid leukemia (AML) and drive leukemic cell growth and survival. Although FLT3 inhibitors have shown considerable promise for the treatment of AML, they ultimately fail to achieve long-term remissions as monotherapy. To identify genetic targets that can sensitize AML cells to killing by FLT3 inhibitors, we performed a genome-wide RNA interference (RNAi)-based screen that identified ATM (ataxia telangiectasia mutated) as being synthetic lethal with FLT3 inhibitor therapy. We found that inactivating ATM or its downstream effector glucose 6-phosphate dehydrogenase (G6PD) sensitizes AML cells to FLT3 inhibitor induced apoptosis. Examination of the cellular metabolome showed that FLT3 inhibition by itself causes profound alterations in central carbon metabolism, resulting in impaired production of the antioxidant factor glutathione, which was further impaired by ATM or G6PD inactivation. Moreover, FLT3 inhibition elicited severe mitochondrial oxidative stress that is causative in apoptosis and is exacerbated by ATM/G6PD inhibition. The use of an agent that intensifies mitochondrial oxidative stress in combination with a FLT3 inhibitor augmented elimination of AML cells in vitro and in vivo, revealing a therapeutic strategy for the improved treatment of FLT3 mutated AML.</description><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Ataxia Telangiectasia Mutated Proteins - antagonists & inhibitors</subject><subject>Ataxia Telangiectasia Mutated Proteins - genetics</subject><subject>Ataxia Telangiectasia Mutated Proteins - metabolism</subject><subject>Benzothiazoles - pharmacology</subject><subject>Biological Sciences</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival - drug effects</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Drug Therapy, Combination</subject><subject>Female</subject><subject>fms-Like Tyrosine Kinase 3 - antagonists & inhibitors</subject><subject>fms-Like Tyrosine Kinase 3 - genetics</subject><subject>fms-Like Tyrosine Kinase 3 - metabolism</subject><subject>Gene Expression Regulation, Leukemic</subject><subject>Genetics</subject><subject>Glucosephosphate Dehydrogenase - antagonists & inhibitors</subject><subject>Glucosephosphate Dehydrogenase - genetics</subject><subject>Glucosephosphate Dehydrogenase - metabolism</subject><subject>Humans</subject><subject>Hydrazines - pharmacology</subject><subject>Kinases</subject><subject>Leukemia</subject><subject>Leukemia, Myeloid, Acute - drug therapy</subject><subject>Leukemia, Myeloid, Acute - genetics</subject><subject>Leukemia, Myeloid, Acute - mortality</subject><subject>Leukemia, Myeloid, Acute - pathology</subject><subject>Metabolism</subject><subject>Mice, Inbred NOD</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>Oxidation-Reduction</subject><subject>Phenylurea Compounds - pharmacology</subject><subject>PNAS Plus</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>RNA, Small Interfering - genetics</subject><subject>RNA, Small Interfering - 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Although FLT3 inhibitors have shown considerable promise for the treatment of AML, they ultimately fail to achieve long-term remissions as monotherapy. To identify genetic targets that can sensitize AML cells to killing by FLT3 inhibitors, we performed a genome-wide RNA interference (RNAi)-based screen that identified ATM (ataxia telangiectasia mutated) as being synthetic lethal with FLT3 inhibitor therapy. We found that inactivating ATM or its downstream effector glucose 6-phosphate dehydrogenase (G6PD) sensitizes AML cells to FLT3 inhibitor induced apoptosis. Examination of the cellular metabolome showed that FLT3 inhibition by itself causes profound alterations in central carbon metabolism, resulting in impaired production of the antioxidant factor glutathione, which was further impaired by ATM or G6PD inactivation. Moreover, FLT3 inhibition elicited severe mitochondrial oxidative stress that is causative in apoptosis and is exacerbated by ATM/G6PD inhibition. 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| subjects | Animals Antineoplastic Agents - pharmacology Ataxia Telangiectasia Mutated Proteins - antagonists & inhibitors Ataxia Telangiectasia Mutated Proteins - genetics Ataxia Telangiectasia Mutated Proteins - metabolism Benzothiazoles - pharmacology Biological Sciences Cell growth Cell Line, Tumor Cell Survival - drug effects Drug Resistance, Neoplasm - genetics Drug Therapy, Combination Female fms-Like Tyrosine Kinase 3 - antagonists & inhibitors fms-Like Tyrosine Kinase 3 - genetics fms-Like Tyrosine Kinase 3 - metabolism Gene Expression Regulation, Leukemic Genetics Glucosephosphate Dehydrogenase - antagonists & inhibitors Glucosephosphate Dehydrogenase - genetics Glucosephosphate Dehydrogenase - metabolism Humans Hydrazines - pharmacology Kinases Leukemia Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - genetics Leukemia, Myeloid, Acute - mortality Leukemia, Myeloid, Acute - pathology Metabolism Mice, Inbred NOD Middle Aged Mutation Oxidation-Reduction Phenylurea Compounds - pharmacology PNAS Plus Protein Kinase Inhibitors - pharmacology RNA, Small Interfering - genetics RNA, Small Interfering - metabolism Signal Transduction Survival Analysis Xenograft Model Antitumor Assays |
| title | ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia |
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