Proto-Oncogenic Role of Mutant IDH2 in Leukemia Initiation and Maintenance
Mutations in the metabolic enzymes isocitrate dehydrogenase-1 (IDH1) and IDH2 that produce the oncometabolite D-2-hydroxyglutarate (2-HG) occur frequently in human acute myeloid leukemia (AML). 2-HG modulates numerous biological pathways implicated in malignant transformation, but the contribution o...
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| Veröffentlicht in: | Cell stem cell 2014-03, Vol.14 (3), p.329-341 |
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| creator | Kats, Lev M. Reschke, Markus Taulli, Riccardo Pozdnyakova, Olga Burgess, Kerri Bhargava, Parul Straley, Kimberly Karnik, Rahul Meissner, Alexander Small, Donald Su, Shinsan M. Yen, Katharine Zhang, Jiangwen Pandolfi, Pier Paolo |
| description | Mutations in the metabolic enzymes isocitrate dehydrogenase-1 (IDH1) and IDH2 that produce the oncometabolite D-2-hydroxyglutarate (2-HG) occur frequently in human acute myeloid leukemia (AML). 2-HG modulates numerous biological pathways implicated in malignant transformation, but the contribution of mutant IDH proteins to maintenance and progression of AML in vivo is currently unknown. To answer this crucial question we have generated transgenic mice that express IDH2R140Q in an on/off- and tissue-specific manner using a tetracycline-inducible system. We found that IDH2R140Q can cooperate with overexpression of HoxA9 and Meis1a and with mutations in FMS-like tyrosine kinase 3 (FLT3) to drive acute leukemia in vivo. Critically, we show that genetic deinduction of mutant IDH2 in leukemic cells in vivo has profound effects on their growth and/or maintenance. Our data demonstrate the proto-oncogenic role of mutant IDH2 and support its relevance as a therapeutic target for the treatment of human AML.
[Display omitted]
•Development of a doxycycline-inducible mouse model of IDH2R140Q•IDH2R140Q drives aberrant self-renewal and a block of differentiation in HSPCs•IDH2R140Q cooperates with Flt3ITD to drive acute leukemia in vivo•IDH2R140Q is essential for leukemia maintenance
Kats et al. show that mutant IDH2 drives self-renewal of HSPCs and cooperates with oncogenes FLT3, HoxA9, and Meis1a to drive initiation of leukemia in vivo. |
| doi_str_mv | 10.1016/j.stem.2013.12.016 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4380188</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S193459091300595X</els_id><sourcerecordid>1520378460</sourcerecordid><originalsourceid>FETCH-LOGICAL-c554t-34797fa0df710311319467065a8f8c22a1d8fb7ee4d187e8ff848d971edfd4a03</originalsourceid><addsrcrecordid>eNp9UU1vFDEMjRCIfsAf4IBy5DJDkslsEgkhodLSRVu1QnCO0sQpWWaSkmQq8e-b1ZYKLj3Zsp-f7fcQekNJTwldvd_2pcLcM0KHnrK-lZ6hQyrF2CkhxPOWq4F3oyLqAB2VsiVkFJSIl-iAcc7JqNQh-nqVU03dZbTpBmKw-FuaACePL5ZqYsXrz-cMh4g3sPyCORi8jqEGU0OK2ESHL0yIFaKJFl6hF95MBV4_xGP04-z0-8l5t7n8sj75tOnsOPLaDVwo4Q1xvh0zUDpQxVeCrEYjvbSMGeqkvxYA3LVfQHovuXRKUHDecUOGY_Rxz3u7XM_gLMSazaRvc5hN_qOTCfr_Tgw_9U2603yQhErZCN49EOT0e4FS9RyKhWkyEdJSNB0ZGYTkq90utofanErJ4B_XUKJ3Juit3pmgdyZoynQrtaG3_x74OPJX9Qb4sAdAk-kuQNbFBmgSupDBVu1SeIr_HmtumLY</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1520378460</pqid></control><display><type>article</type><title>Proto-Oncogenic Role of Mutant IDH2 in Leukemia Initiation and Maintenance</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals Complete</source><source>Cell Press Free Archives</source><source>EZB-FREE-00999 freely available EZB journals</source><creator>Kats, Lev M. ; Reschke, Markus ; Taulli, Riccardo ; Pozdnyakova, Olga ; Burgess, Kerri ; Bhargava, Parul ; Straley, Kimberly ; Karnik, Rahul ; Meissner, Alexander ; Small, Donald ; Su, Shinsan M. ; Yen, Katharine ; Zhang, Jiangwen ; Pandolfi, Pier Paolo</creator><creatorcontrib>Kats, Lev M. ; Reschke, Markus ; Taulli, Riccardo ; Pozdnyakova, Olga ; Burgess, Kerri ; Bhargava, Parul ; Straley, Kimberly ; Karnik, Rahul ; Meissner, Alexander ; Small, Donald ; Su, Shinsan M. ; Yen, Katharine ; Zhang, Jiangwen ; Pandolfi, Pier Paolo</creatorcontrib><description>Mutations in the metabolic enzymes isocitrate dehydrogenase-1 (IDH1) and IDH2 that produce the oncometabolite D-2-hydroxyglutarate (2-HG) occur frequently in human acute myeloid leukemia (AML). 2-HG modulates numerous biological pathways implicated in malignant transformation, but the contribution of mutant IDH proteins to maintenance and progression of AML in vivo is currently unknown. To answer this crucial question we have generated transgenic mice that express IDH2R140Q in an on/off- and tissue-specific manner using a tetracycline-inducible system. We found that IDH2R140Q can cooperate with overexpression of HoxA9 and Meis1a and with mutations in FMS-like tyrosine kinase 3 (FLT3) to drive acute leukemia in vivo. Critically, we show that genetic deinduction of mutant IDH2 in leukemic cells in vivo has profound effects on their growth and/or maintenance. Our data demonstrate the proto-oncogenic role of mutant IDH2 and support its relevance as a therapeutic target for the treatment of human AML.
[Display omitted]
•Development of a doxycycline-inducible mouse model of IDH2R140Q•IDH2R140Q drives aberrant self-renewal and a block of differentiation in HSPCs•IDH2R140Q cooperates with Flt3ITD to drive acute leukemia in vivo•IDH2R140Q is essential for leukemia maintenance
Kats et al. show that mutant IDH2 drives self-renewal of HSPCs and cooperates with oncogenes FLT3, HoxA9, and Meis1a to drive initiation of leukemia in vivo.</description><identifier>ISSN: 1934-5909</identifier><identifier>EISSN: 1875-9777</identifier><identifier>DOI: 10.1016/j.stem.2013.12.016</identifier><identifier>PMID: 24440599</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Bone Marrow - pathology ; Carcinogenesis - genetics ; Carcinogenesis - pathology ; Cell Differentiation ; Cell Proliferation ; Cell Transformation, Neoplastic - pathology ; Disease Models, Animal ; Erythroid Cells - metabolism ; Erythroid Cells - pathology ; fms-Like Tyrosine Kinase 3 - metabolism ; Hematopoiesis ; Hematopoietic Stem Cells - pathology ; Homeodomain Proteins - metabolism ; Isocitrate Dehydrogenase - genetics ; Isocitrate Dehydrogenase - metabolism ; Leukemia, Myeloid, Acute - genetics ; Leukemia, Myeloid, Acute - pathology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation - genetics ; Myeloid Ecotropic Viral Integration Site 1 Protein ; Neoplasm Proteins - metabolism ; Oncogenes ; Spleen - pathology ; Transcription, Genetic</subject><ispartof>Cell stem cell, 2014-03, Vol.14 (3), p.329-341</ispartof><rights>2014 Elsevier Inc.</rights><rights>Copyright © 2014 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c554t-34797fa0df710311319467065a8f8c22a1d8fb7ee4d187e8ff848d971edfd4a03</citedby><cites>FETCH-LOGICAL-c554t-34797fa0df710311319467065a8f8c22a1d8fb7ee4d187e8ff848d971edfd4a03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.stem.2013.12.016$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24440599$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kats, Lev M.</creatorcontrib><creatorcontrib>Reschke, Markus</creatorcontrib><creatorcontrib>Taulli, Riccardo</creatorcontrib><creatorcontrib>Pozdnyakova, Olga</creatorcontrib><creatorcontrib>Burgess, Kerri</creatorcontrib><creatorcontrib>Bhargava, Parul</creatorcontrib><creatorcontrib>Straley, Kimberly</creatorcontrib><creatorcontrib>Karnik, Rahul</creatorcontrib><creatorcontrib>Meissner, Alexander</creatorcontrib><creatorcontrib>Small, Donald</creatorcontrib><creatorcontrib>Su, Shinsan M.</creatorcontrib><creatorcontrib>Yen, Katharine</creatorcontrib><creatorcontrib>Zhang, Jiangwen</creatorcontrib><creatorcontrib>Pandolfi, Pier Paolo</creatorcontrib><title>Proto-Oncogenic Role of Mutant IDH2 in Leukemia Initiation and Maintenance</title><title>Cell stem cell</title><addtitle>Cell Stem Cell</addtitle><description>Mutations in the metabolic enzymes isocitrate dehydrogenase-1 (IDH1) and IDH2 that produce the oncometabolite D-2-hydroxyglutarate (2-HG) occur frequently in human acute myeloid leukemia (AML). 2-HG modulates numerous biological pathways implicated in malignant transformation, but the contribution of mutant IDH proteins to maintenance and progression of AML in vivo is currently unknown. To answer this crucial question we have generated transgenic mice that express IDH2R140Q in an on/off- and tissue-specific manner using a tetracycline-inducible system. We found that IDH2R140Q can cooperate with overexpression of HoxA9 and Meis1a and with mutations in FMS-like tyrosine kinase 3 (FLT3) to drive acute leukemia in vivo. Critically, we show that genetic deinduction of mutant IDH2 in leukemic cells in vivo has profound effects on their growth and/or maintenance. Our data demonstrate the proto-oncogenic role of mutant IDH2 and support its relevance as a therapeutic target for the treatment of human AML.
[Display omitted]
•Development of a doxycycline-inducible mouse model of IDH2R140Q•IDH2R140Q drives aberrant self-renewal and a block of differentiation in HSPCs•IDH2R140Q cooperates with Flt3ITD to drive acute leukemia in vivo•IDH2R140Q is essential for leukemia maintenance
Kats et al. show that mutant IDH2 drives self-renewal of HSPCs and cooperates with oncogenes FLT3, HoxA9, and Meis1a to drive initiation of leukemia in vivo.</description><subject>Animals</subject><subject>Bone Marrow - pathology</subject><subject>Carcinogenesis - genetics</subject><subject>Carcinogenesis - pathology</subject><subject>Cell Differentiation</subject><subject>Cell Proliferation</subject><subject>Cell Transformation, Neoplastic - pathology</subject><subject>Disease Models, Animal</subject><subject>Erythroid Cells - metabolism</subject><subject>Erythroid Cells - pathology</subject><subject>fms-Like Tyrosine Kinase 3 - metabolism</subject><subject>Hematopoiesis</subject><subject>Hematopoietic Stem Cells - pathology</subject><subject>Homeodomain Proteins - metabolism</subject><subject>Isocitrate Dehydrogenase - genetics</subject><subject>Isocitrate Dehydrogenase - metabolism</subject><subject>Leukemia, Myeloid, Acute - genetics</subject><subject>Leukemia, Myeloid, Acute - pathology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Transgenic</subject><subject>Mutation - genetics</subject><subject>Myeloid Ecotropic Viral Integration Site 1 Protein</subject><subject>Neoplasm Proteins - metabolism</subject><subject>Oncogenes</subject><subject>Spleen - pathology</subject><subject>Transcription, Genetic</subject><issn>1934-5909</issn><issn>1875-9777</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UU1vFDEMjRCIfsAf4IBy5DJDkslsEgkhodLSRVu1QnCO0sQpWWaSkmQq8e-b1ZYKLj3Zsp-f7fcQekNJTwldvd_2pcLcM0KHnrK-lZ6hQyrF2CkhxPOWq4F3oyLqAB2VsiVkFJSIl-iAcc7JqNQh-nqVU03dZbTpBmKw-FuaACePL5ZqYsXrz-cMh4g3sPyCORi8jqEGU0OK2ESHL0yIFaKJFl6hF95MBV4_xGP04-z0-8l5t7n8sj75tOnsOPLaDVwo4Q1xvh0zUDpQxVeCrEYjvbSMGeqkvxYA3LVfQHovuXRKUHDecUOGY_Rxz3u7XM_gLMSazaRvc5hN_qOTCfr_Tgw_9U2603yQhErZCN49EOT0e4FS9RyKhWkyEdJSNB0ZGYTkq90utofanErJ4B_XUKJ3Juit3pmgdyZoynQrtaG3_x74OPJX9Qb4sAdAk-kuQNbFBmgSupDBVu1SeIr_HmtumLY</recordid><startdate>20140306</startdate><enddate>20140306</enddate><creator>Kats, Lev M.</creator><creator>Reschke, Markus</creator><creator>Taulli, Riccardo</creator><creator>Pozdnyakova, Olga</creator><creator>Burgess, Kerri</creator><creator>Bhargava, Parul</creator><creator>Straley, Kimberly</creator><creator>Karnik, Rahul</creator><creator>Meissner, Alexander</creator><creator>Small, Donald</creator><creator>Su, Shinsan M.</creator><creator>Yen, Katharine</creator><creator>Zhang, Jiangwen</creator><creator>Pandolfi, Pier Paolo</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><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>7QO</scope><scope>7T5</scope><scope>7TO</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>5PM</scope></search><sort><creationdate>20140306</creationdate><title>Proto-Oncogenic Role of Mutant IDH2 in Leukemia Initiation and Maintenance</title><author>Kats, Lev M. ; Reschke, Markus ; Taulli, Riccardo ; Pozdnyakova, Olga ; Burgess, Kerri ; Bhargava, Parul ; Straley, Kimberly ; Karnik, Rahul ; Meissner, Alexander ; Small, Donald ; Su, Shinsan M. ; Yen, Katharine ; Zhang, Jiangwen ; Pandolfi, Pier Paolo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c554t-34797fa0df710311319467065a8f8c22a1d8fb7ee4d187e8ff848d971edfd4a03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Bone Marrow - pathology</topic><topic>Carcinogenesis - genetics</topic><topic>Carcinogenesis - pathology</topic><topic>Cell Differentiation</topic><topic>Cell Proliferation</topic><topic>Cell Transformation, Neoplastic - pathology</topic><topic>Disease Models, Animal</topic><topic>Erythroid Cells - metabolism</topic><topic>Erythroid Cells - pathology</topic><topic>fms-Like Tyrosine Kinase 3 - metabolism</topic><topic>Hematopoiesis</topic><topic>Hematopoietic Stem Cells - pathology</topic><topic>Homeodomain Proteins - metabolism</topic><topic>Isocitrate Dehydrogenase - genetics</topic><topic>Isocitrate Dehydrogenase - metabolism</topic><topic>Leukemia, Myeloid, Acute - genetics</topic><topic>Leukemia, Myeloid, Acute - pathology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Transgenic</topic><topic>Mutation - genetics</topic><topic>Myeloid Ecotropic Viral Integration Site 1 Protein</topic><topic>Neoplasm Proteins - metabolism</topic><topic>Oncogenes</topic><topic>Spleen - pathology</topic><topic>Transcription, Genetic</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kats, Lev M.</creatorcontrib><creatorcontrib>Reschke, Markus</creatorcontrib><creatorcontrib>Taulli, Riccardo</creatorcontrib><creatorcontrib>Pozdnyakova, Olga</creatorcontrib><creatorcontrib>Burgess, Kerri</creatorcontrib><creatorcontrib>Bhargava, Parul</creatorcontrib><creatorcontrib>Straley, Kimberly</creatorcontrib><creatorcontrib>Karnik, Rahul</creatorcontrib><creatorcontrib>Meissner, Alexander</creatorcontrib><creatorcontrib>Small, Donald</creatorcontrib><creatorcontrib>Su, Shinsan M.</creatorcontrib><creatorcontrib>Yen, Katharine</creatorcontrib><creatorcontrib>Zhang, Jiangwen</creatorcontrib><creatorcontrib>Pandolfi, Pier Paolo</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Immunology Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell stem cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kats, Lev M.</au><au>Reschke, Markus</au><au>Taulli, Riccardo</au><au>Pozdnyakova, Olga</au><au>Burgess, Kerri</au><au>Bhargava, Parul</au><au>Straley, Kimberly</au><au>Karnik, Rahul</au><au>Meissner, Alexander</au><au>Small, Donald</au><au>Su, Shinsan M.</au><au>Yen, Katharine</au><au>Zhang, Jiangwen</au><au>Pandolfi, Pier Paolo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Proto-Oncogenic Role of Mutant IDH2 in Leukemia Initiation and Maintenance</atitle><jtitle>Cell stem cell</jtitle><addtitle>Cell Stem Cell</addtitle><date>2014-03-06</date><risdate>2014</risdate><volume>14</volume><issue>3</issue><spage>329</spage><epage>341</epage><pages>329-341</pages><issn>1934-5909</issn><eissn>1875-9777</eissn><abstract>Mutations in the metabolic enzymes isocitrate dehydrogenase-1 (IDH1) and IDH2 that produce the oncometabolite D-2-hydroxyglutarate (2-HG) occur frequently in human acute myeloid leukemia (AML). 2-HG modulates numerous biological pathways implicated in malignant transformation, but the contribution of mutant IDH proteins to maintenance and progression of AML in vivo is currently unknown. To answer this crucial question we have generated transgenic mice that express IDH2R140Q in an on/off- and tissue-specific manner using a tetracycline-inducible system. We found that IDH2R140Q can cooperate with overexpression of HoxA9 and Meis1a and with mutations in FMS-like tyrosine kinase 3 (FLT3) to drive acute leukemia in vivo. Critically, we show that genetic deinduction of mutant IDH2 in leukemic cells in vivo has profound effects on their growth and/or maintenance. Our data demonstrate the proto-oncogenic role of mutant IDH2 and support its relevance as a therapeutic target for the treatment of human AML.
[Display omitted]
•Development of a doxycycline-inducible mouse model of IDH2R140Q•IDH2R140Q drives aberrant self-renewal and a block of differentiation in HSPCs•IDH2R140Q cooperates with Flt3ITD to drive acute leukemia in vivo•IDH2R140Q is essential for leukemia maintenance
Kats et al. show that mutant IDH2 drives self-renewal of HSPCs and cooperates with oncogenes FLT3, HoxA9, and Meis1a to drive initiation of leukemia in vivo.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>24440599</pmid><doi>10.1016/j.stem.2013.12.016</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete; Cell Press Free Archives; EZB-FREE-00999 freely available EZB journals |
| subjects | Animals Bone Marrow - pathology Carcinogenesis - genetics Carcinogenesis - pathology Cell Differentiation Cell Proliferation Cell Transformation, Neoplastic - pathology Disease Models, Animal Erythroid Cells - metabolism Erythroid Cells - pathology fms-Like Tyrosine Kinase 3 - metabolism Hematopoiesis Hematopoietic Stem Cells - pathology Homeodomain Proteins - metabolism Isocitrate Dehydrogenase - genetics Isocitrate Dehydrogenase - metabolism Leukemia, Myeloid, Acute - genetics Leukemia, Myeloid, Acute - pathology Mice Mice, Inbred C57BL Mice, Transgenic Mutation - genetics Myeloid Ecotropic Viral Integration Site 1 Protein Neoplasm Proteins - metabolism Oncogenes Spleen - pathology Transcription, Genetic |
| title | Proto-Oncogenic Role of Mutant IDH2 in Leukemia Initiation and Maintenance |
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