Proto-oncogenic role of mutant IDH2 in leukemia initiation and maintenance

Lev M. Kats; Markus Reschke; Riccardo Taulli; Olga Pozdnyakova; Kerri Burgess; Parul Bhargava; Kimberly Straley; Rahul Karnik; Alexander Meissner; Donald Small; Shinsan M. Su; Katharine Yen; Jiangwen Zhang; Pier Paolo Pandolfi

doi:10.1016/j.stem.2013.12.016

Proto-oncogenic role of mutant IDH2 in leukemia initiation and maintenance

Lev M. Kats, Markus Reschke, Riccardo Taulli, Olga Pozdnyakova, Kerri Burgess, Parul Bhargava, Kimberly Straley, Rahul Karnik, Alexander Meissner, Donald Small, Shinsan M. Su, Katharine Yen, Jiangwen Zhang, Pier Paolo Pandolfi

School of Medicine

Research output: Contribution to journal › Article › peer-review

126 Scopus citations

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 IDH2^R140Q in an on/off- and tissue-specific manner using a tetracycline-inducible system. We found that IDH2^R140Q 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.

Original language	English (US)
Pages (from-to)	329-341
Number of pages	13
Journal	Cell stem cell
Volume	14
Issue number	3
DOIs	https://doi.org/10.1016/j.stem.2013.12.016
State	Published - Mar 6 2014

ASJC Scopus subject areas

Molecular Medicine
Genetics
Cell Biology

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@article{2b4f5f13c1df4ddfbc2308c20ac36cbb,

title = "Proto-oncogenic role of mutant IDH2 in leukemia initiation and maintenance",

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.",

author = "Kats, {Lev M.} and Markus Reschke and Riccardo Taulli and Olga Pozdnyakova and Kerri Burgess and Parul Bhargava and Kimberly Straley and Rahul Karnik and Alexander Meissner and Donald Small and Su, {Shinsan M.} and Katharine Yen and Jiangwen Zhang and Pandolfi, {Pier Paolo}",

note = "Funding Information: We thank Dr. Robert Welner, Dr. Christian Bach, and members of the Pandolfi laboratory for critical discussion. L.M.K. was supported by an Overseas Postdoctoral Fellowship from the National Health and Research Council of Australia. M.R. was supported by the German Academy of Sciences Leopoldina (Leopoldina Research Fellowship grant number: LPDS 2009-27). R.T. was supported by a Marie Curie International Outgoing Fellowship for Career Development. K.Y., M.S., and K.S. are employees and shareholders of Agios Pharmaceuticals. ",

year = "2014",

month = mar,

day = "6",

doi = "10.1016/j.stem.2013.12.016",

language = "English (US)",

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pages = "329--341",

journal = "Cell Stem Cell",

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T1 - Proto-oncogenic role of mutant IDH2 in leukemia initiation and maintenance

AU - Kats, Lev M.

AU - Reschke, Markus

AU - Taulli, Riccardo

AU - Pozdnyakova, Olga

AU - Burgess, Kerri

AU - Bhargava, Parul

AU - Straley, Kimberly

AU - Karnik, Rahul

AU - Meissner, Alexander

AU - Small, Donald

AU - Su, Shinsan M.

AU - Yen, Katharine

AU - Zhang, Jiangwen

AU - Pandolfi, Pier Paolo

N1 - Funding Information: We thank Dr. Robert Welner, Dr. Christian Bach, and members of the Pandolfi laboratory for critical discussion. L.M.K. was supported by an Overseas Postdoctoral Fellowship from the National Health and Research Council of Australia. M.R. was supported by the German Academy of Sciences Leopoldina (Leopoldina Research Fellowship grant number: LPDS 2009-27). R.T. was supported by a Marie Curie International Outgoing Fellowship for Career Development. K.Y., M.S., and K.S. are employees and shareholders of Agios Pharmaceuticals.

PY - 2014/3/6

Y1 - 2014/3/6

N2 - 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.

AB - 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.

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JO - Cell Stem Cell

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ER -

Proto-oncogenic role of mutant IDH2 in leukemia initiation and maintenance

Abstract

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