Pathological glycogenesis through glycogen synthase 1 and suppression of excessive AMP kinase activity in myeloid leukemia cells
The rapid proliferation of myeloid leukemia cells is highly dependent on increased glucose metabolism. Through an unbiased metabolomics analysis of leukemia cells, we found that the glycogenic precursor UDP-D-glucose is pervasively upregulated, despite low glycogen levels. Targeting the rate-limitin...
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| Veröffentlicht in: | Leukemia 2015-07, Vol.29 (7), p.1555-1563 |
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| creator | Bhanot, H Reddy, M M Nonami, A Weisberg, E L Bonal, D Kirschmeier, P T Salgia, S Podar, K Galinsky, I Chowdary, T K Neuberg, D Tonon, G Stone, R M Asara, J Griffin, J D Sattler, M |
| description | The rapid proliferation of myeloid leukemia cells is highly dependent on increased glucose metabolism. Through an unbiased metabolomics analysis of leukemia cells, we found that the glycogenic precursor UDP-D-glucose is pervasively upregulated, despite low glycogen levels. Targeting the rate-limiting glycogen synthase 1 (GYS1) not only decreased glycolytic flux but also increased activation of the glycogen-responsive AMP kinase (AMPK), leading to significant growth suppression. Further, genetic and pharmacological hyper-activation of AMPK was sufficient to induce the changes observed with GYS1 targeting. Cancer genomics data also indicate that elevated levels of the glycogenic enzymes GYS1/2 or GBE1 (glycogen branching enzyme 1) are associated with poor survival in AML. These results suggest a novel mechanism whereby leukemic cells sustain aberrant proliferation by suppressing excess AMPK activity through elevated glycogenic flux and provide a therapeutic entry point for targeting leukemia cell metabolism. |
| doi_str_mv | 10.1038/leu.2015.46 |
| format | Article |
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Through an unbiased metabolomics analysis of leukemia cells, we found that the glycogenic precursor UDP-D-glucose is pervasively upregulated, despite low glycogen levels. Targeting the rate-limiting glycogen synthase 1 (GYS1) not only decreased glycolytic flux but also increased activation of the glycogen-responsive AMP kinase (AMPK), leading to significant growth suppression. Further, genetic and pharmacological hyper-activation of AMPK was sufficient to induce the changes observed with GYS1 targeting. Cancer genomics data also indicate that elevated levels of the glycogenic enzymes GYS1/2 or GBE1 (glycogen branching enzyme 1) are associated with poor survival in AML. These results suggest a novel mechanism whereby leukemic cells sustain aberrant proliferation by suppressing excess AMPK activity through elevated glycogenic flux and provide a therapeutic entry point for targeting leukemia cell metabolism.</description><identifier>ISSN: 0887-6924</identifier><identifier>EISSN: 1476-5551</identifier><identifier>DOI: 10.1038/leu.2015.46</identifier><identifier>PMID: 25703587</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/95 ; 631/443/319/320 ; 631/67/1059/602 ; 631/67/1990/283 ; 631/67/1990/283/1897 ; 631/80/86 ; 64/60 ; Activation ; Acute myeloid leukemia ; AMP-Activated Protein Kinases - metabolism ; Animals ; Apoptosis ; Cancer ; Cancer cells ; Cancer Research ; Case-Control Studies ; Cell growth ; Cell Proliferation ; Critical Care Medicine ; Development and progression ; Energy consumption ; Enzymes ; Flow Cytometry ; Genetic aspects ; Genomics ; Glucose ; Glucose metabolism ; Glycogen ; Glycogen - biosynthesis ; Glycogen branching enzyme ; Glycogen synthase ; Glycogen Synthase - antagonists & inhibitors ; Glycogen Synthase - genetics ; Glycogen Synthase - metabolism ; Glycogens ; Glycolysis ; Health aspects ; HEK293 Cells ; Hematology ; Humans ; Intensive ; Internal Medicine ; Kinases ; Leukemia ; Leukemia, Myeloid - metabolism ; Leukemia, Myeloid - mortality ; Leukemia, Myeloid - pathology ; Medical research ; Medicine ; Medicine & Public Health ; Metabolism ; Metabolomics ; Mice ; Myelocytic leukemia ; Myeloid leukemia ; Nonlymphoid leukemia ; Oncology ; original-article ; Phosphorylation ; Physiological aspects ; Prognosis ; Protein kinases ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Messenger - genetics ; RNA, Small Interfering - genetics ; Science education ; Signal transduction ; Survival Rate ; Transferases ; Tumor Cells, Cultured</subject><ispartof>Leukemia, 2015-07, Vol.29 (7), p.1555-1563</ispartof><rights>Macmillan Publishers Limited 2015</rights><rights>COPYRIGHT 2015 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jul 2015</rights><rights>Macmillan Publishers Limited 2015.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c706t-7bba268f6b906c9a9ec406393de593b313d32b404b5a94c996555e5e6e4e310b3</citedby><cites>FETCH-LOGICAL-c706t-7bba268f6b906c9a9ec406393de593b313d32b404b5a94c996555e5e6e4e310b3</cites><orcidid>0000-0003-2566-3145</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/leu.2015.46$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/leu.2015.46$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27903,27904,41467,42536,51298</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25703587$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bhanot, H</creatorcontrib><creatorcontrib>Reddy, M M</creatorcontrib><creatorcontrib>Nonami, A</creatorcontrib><creatorcontrib>Weisberg, E L</creatorcontrib><creatorcontrib>Bonal, D</creatorcontrib><creatorcontrib>Kirschmeier, P T</creatorcontrib><creatorcontrib>Salgia, S</creatorcontrib><creatorcontrib>Podar, K</creatorcontrib><creatorcontrib>Galinsky, I</creatorcontrib><creatorcontrib>Chowdary, T K</creatorcontrib><creatorcontrib>Neuberg, D</creatorcontrib><creatorcontrib>Tonon, G</creatorcontrib><creatorcontrib>Stone, R M</creatorcontrib><creatorcontrib>Asara, J</creatorcontrib><creatorcontrib>Griffin, J D</creatorcontrib><creatorcontrib>Sattler, M</creatorcontrib><title>Pathological glycogenesis through glycogen synthase 1 and suppression of excessive AMP kinase activity in myeloid leukemia cells</title><title>Leukemia</title><addtitle>Leukemia</addtitle><addtitle>Leukemia</addtitle><description>The rapid proliferation of myeloid leukemia cells is highly dependent on increased glucose metabolism. Through an unbiased metabolomics analysis of leukemia cells, we found that the glycogenic precursor UDP-D-glucose is pervasively upregulated, despite low glycogen levels. Targeting the rate-limiting glycogen synthase 1 (GYS1) not only decreased glycolytic flux but also increased activation of the glycogen-responsive AMP kinase (AMPK), leading to significant growth suppression. Further, genetic and pharmacological hyper-activation of AMPK was sufficient to induce the changes observed with GYS1 targeting. Cancer genomics data also indicate that elevated levels of the glycogenic enzymes GYS1/2 or GBE1 (glycogen branching enzyme 1) are associated with poor survival in AML. These results suggest a novel mechanism whereby leukemic cells sustain aberrant proliferation by suppressing excess AMPK activity through elevated glycogenic flux and provide a therapeutic entry point for targeting leukemia cell metabolism.</description><subject>13/95</subject><subject>631/443/319/320</subject><subject>631/67/1059/602</subject><subject>631/67/1990/283</subject><subject>631/67/1990/283/1897</subject><subject>631/80/86</subject><subject>64/60</subject><subject>Activation</subject><subject>Acute myeloid leukemia</subject><subject>AMP-Activated Protein Kinases - metabolism</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Cancer</subject><subject>Cancer cells</subject><subject>Cancer Research</subject><subject>Case-Control Studies</subject><subject>Cell growth</subject><subject>Cell Proliferation</subject><subject>Critical Care Medicine</subject><subject>Development and progression</subject><subject>Energy consumption</subject><subject>Enzymes</subject><subject>Flow Cytometry</subject><subject>Genetic aspects</subject><subject>Genomics</subject><subject>Glucose</subject><subject>Glucose metabolism</subject><subject>Glycogen</subject><subject>Glycogen - biosynthesis</subject><subject>Glycogen branching enzyme</subject><subject>Glycogen synthase</subject><subject>Glycogen Synthase - antagonists & inhibitors</subject><subject>Glycogen Synthase - genetics</subject><subject>Glycogen Synthase - metabolism</subject><subject>Glycogens</subject><subject>Glycolysis</subject><subject>Health aspects</subject><subject>HEK293 Cells</subject><subject>Hematology</subject><subject>Humans</subject><subject>Intensive</subject><subject>Internal Medicine</subject><subject>Kinases</subject><subject>Leukemia</subject><subject>Leukemia, Myeloid - metabolism</subject><subject>Leukemia, Myeloid - mortality</subject><subject>Leukemia, Myeloid - pathology</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metabolism</subject><subject>Metabolomics</subject><subject>Mice</subject><subject>Myelocytic leukemia</subject><subject>Myeloid leukemia</subject><subject>Nonlymphoid leukemia</subject><subject>Oncology</subject><subject>original-article</subject><subject>Phosphorylation</subject><subject>Physiological aspects</subject><subject>Prognosis</subject><subject>Protein kinases</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Small Interfering - genetics</subject><subject>Science education</subject><subject>Signal transduction</subject><subject>Survival Rate</subject><subject>Transferases</subject><subject>Tumor Cells, Cultured</subject><issn>0887-6924</issn><issn>1476-5551</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</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>eNqFkk2LFDEQhhtR3HH15F0Cggg6Y74zuQjD4hesuAc9h3S6uju7Pclsp3twbv5008w6zsrikkNI1ZM3qXqrKJ4TvCCYLd91MC4oJmLB5YNiRriScyEEeVjM8HKp5lJTflI8SekS4ykpHxcnVCjMxFLNil8XdmhjFxvvbIeabudiAwGST2ho-zg27SGI0i4MrU2ACLKhQmncbHpIyceAYo3gp5sOW0CrrxfoyoeJtG7wWz_skA9ovYMu-grl_17B2lvkoOvS0-JRbbsEz2720-LHxw_fzz7Pz799-nK2Op87heUwV2VpqVzWstRYOm01OI4l06wCoVnJCKsYLTnmpbCaO61l7gEIkMCBEVyy0-L9XnczlmuoHISht53Z9H5t-52J1pvbmeBb08St4VyrpRBZ4PWNQB-vR0iDWfs0lWADxDEZoiglCmOt7kelFkQzyif05T_oZRz7kDthKGNEMqw5-x-VtbjCVAn-l2psB8aHOuZC3PS0WXFKNJ66kqnFHVReVTbFxQC1z_FbF14dXWjBdkObYjcO2fhkVpJgijmT7D7wWPHNHnR9TKmH-mADwWaaaZNnxEwzbbjM9Itj5w7snyHOwNs9kHIqNNAfdecOvd_Jkf7n</recordid><startdate>20150701</startdate><enddate>20150701</enddate><creator>Bhanot, H</creator><creator>Reddy, M M</creator><creator>Nonami, A</creator><creator>Weisberg, E L</creator><creator>Bonal, D</creator><creator>Kirschmeier, P T</creator><creator>Salgia, S</creator><creator>Podar, K</creator><creator>Galinsky, I</creator><creator>Chowdary, T K</creator><creator>Neuberg, D</creator><creator>Tonon, G</creator><creator>Stone, R M</creator><creator>Asara, J</creator><creator>Griffin, J D</creator><creator>Sattler, M</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>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-2566-3145</orcidid></search><sort><creationdate>20150701</creationdate><title>Pathological glycogenesis through glycogen synthase 1 and suppression of excessive AMP kinase activity in myeloid leukemia cells</title><author>Bhanot, H ; Reddy, M M ; Nonami, A ; Weisberg, E L ; Bonal, D ; Kirschmeier, P T ; Salgia, S ; Podar, K ; Galinsky, I ; Chowdary, T K ; Neuberg, D ; Tonon, G ; Stone, R M ; Asara, J ; Griffin, J D ; Sattler, M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c706t-7bba268f6b906c9a9ec406393de593b313d32b404b5a94c996555e5e6e4e310b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>13/95</topic><topic>631/443/319/320</topic><topic>631/67/1059/602</topic><topic>631/67/1990/283</topic><topic>631/67/1990/283/1897</topic><topic>631/80/86</topic><topic>64/60</topic><topic>Activation</topic><topic>Acute myeloid leukemia</topic><topic>AMP-Activated Protein Kinases - metabolism</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Cancer</topic><topic>Cancer cells</topic><topic>Cancer Research</topic><topic>Case-Control Studies</topic><topic>Cell growth</topic><topic>Cell Proliferation</topic><topic>Critical Care Medicine</topic><topic>Development and progression</topic><topic>Energy consumption</topic><topic>Enzymes</topic><topic>Flow Cytometry</topic><topic>Genetic aspects</topic><topic>Genomics</topic><topic>Glucose</topic><topic>Glucose metabolism</topic><topic>Glycogen</topic><topic>Glycogen - biosynthesis</topic><topic>Glycogen branching enzyme</topic><topic>Glycogen synthase</topic><topic>Glycogen Synthase - antagonists & inhibitors</topic><topic>Glycogen Synthase - genetics</topic><topic>Glycogen Synthase - metabolism</topic><topic>Glycogens</topic><topic>Glycolysis</topic><topic>Health aspects</topic><topic>HEK293 Cells</topic><topic>Hematology</topic><topic>Humans</topic><topic>Intensive</topic><topic>Internal Medicine</topic><topic>Kinases</topic><topic>Leukemia</topic><topic>Leukemia, Myeloid - 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Through an unbiased metabolomics analysis of leukemia cells, we found that the glycogenic precursor UDP-D-glucose is pervasively upregulated, despite low glycogen levels. Targeting the rate-limiting glycogen synthase 1 (GYS1) not only decreased glycolytic flux but also increased activation of the glycogen-responsive AMP kinase (AMPK), leading to significant growth suppression. Further, genetic and pharmacological hyper-activation of AMPK was sufficient to induce the changes observed with GYS1 targeting. Cancer genomics data also indicate that elevated levels of the glycogenic enzymes GYS1/2 or GBE1 (glycogen branching enzyme 1) are associated with poor survival in AML. These results suggest a novel mechanism whereby leukemic cells sustain aberrant proliferation by suppressing excess AMPK activity through elevated glycogenic flux and provide a therapeutic entry point for targeting leukemia cell metabolism.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>25703587</pmid><doi>10.1038/leu.2015.46</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0003-2566-3145</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0887-6924 |
| ispartof | Leukemia, 2015-07, Vol.29 (7), p.1555-1563 |
| issn | 0887-6924 1476-5551 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4497855 |
| source | MEDLINE; Nature Journals Online; EZB-FREE-00999 freely available EZB journals; SpringerLink Journals - AutoHoldings |
| subjects | 13/95 631/443/319/320 631/67/1059/602 631/67/1990/283 631/67/1990/283/1897 631/80/86 64/60 Activation Acute myeloid leukemia AMP-Activated Protein Kinases - metabolism Animals Apoptosis Cancer Cancer cells Cancer Research Case-Control Studies Cell growth Cell Proliferation Critical Care Medicine Development and progression Energy consumption Enzymes Flow Cytometry Genetic aspects Genomics Glucose Glucose metabolism Glycogen Glycogen - biosynthesis Glycogen branching enzyme Glycogen synthase Glycogen Synthase - antagonists & inhibitors Glycogen Synthase - genetics Glycogen Synthase - metabolism Glycogens Glycolysis Health aspects HEK293 Cells Hematology Humans Intensive Internal Medicine Kinases Leukemia Leukemia, Myeloid - metabolism Leukemia, Myeloid - mortality Leukemia, Myeloid - pathology Medical research Medicine Medicine & Public Health Metabolism Metabolomics Mice Myelocytic leukemia Myeloid leukemia Nonlymphoid leukemia Oncology original-article Phosphorylation Physiological aspects Prognosis Protein kinases Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger - genetics RNA, Small Interfering - genetics Science education Signal transduction Survival Rate Transferases Tumor Cells, Cultured |
| title | Pathological glycogenesis through glycogen synthase 1 and suppression of excessive AMP kinase activity in myeloid leukemia cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-22T05%3A25%3A02IST&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=Pathological%20glycogenesis%20through%20glycogen%20synthase%201%20and%20suppression%20of%20excessive%20AMP%20kinase%20activity%20in%20myeloid%20leukemia%20cells&rft.jtitle=Leukemia&rft.au=Bhanot,%20H&rft.date=2015-07-01&rft.volume=29&rft.issue=7&rft.spage=1555&rft.epage=1563&rft.pages=1555-1563&rft.issn=0887-6924&rft.eissn=1476-5551&rft_id=info:doi/10.1038/leu.2015.46&rft_dat=%3Cgale_pubme%3EA421909965%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=1694702754&rft_id=info:pmid/25703587&rft_galeid=A421909965&rfr_iscdi=true |