Enantiomer-specific and paracrine leukemogenicity of mutant IDH metabolite 2-hydroxyglutarate.

2.50
Hdl Handle:
http://hdl.handle.net/10033/621098
Title:
Enantiomer-specific and paracrine leukemogenicity of mutant IDH metabolite 2-hydroxyglutarate.
Authors:
Chaturvedi, A; Araujo Cruz, M M; Jyotsana, N; Sharma, A; Goparaju, R; Schwarzer, A; Görlich, K; Schottmann, R; Struys, E A; Jansen, E E; Rohde, C; Müller-Tidow, C; Geffers, R. ( 0000-0003-4409-016X ) ; Göhring, G; Ganser, A; Thol, F; Heuser, M
Abstract:
Canonical mutations in IDH1 and IDH2 produce high levels of the R-enantiomer of 2-hydroxyglutarate (R-2HG), which is a competitive inhibitor of α-ketoglutarate (αKG)-dependent enzymes and a putative oncometabolite. Mutant IDH1 collaborates with HoxA9 to induce monocytic leukemia in vivo. We used two mouse models and a patient-derived acute myeloid leukemia xenotransplantation (PDX) model to evaluate the in vivo transforming potential of R-2HG, S-2HG and αKG independent of the mutant IDH1 protein. We show that R-2HG, but not S-2HG or αKG, is an oncometabolite in vivo that does not require the mutant IDH1 protein to induce hyperleukocytosis and to accelerate the onset of murine and human leukemia. Thus, circulating R-2HG acts in a paracrine manner and can drive the expansion of many different leukemic and preleukemic clones that may express wild-type IDH1, and therefore can be a driver of clonal evolution and diversity. In addition, we show that the mutant IDH1 protein is a stronger oncogene than R-2HG alone when comparable intracellular R-2HG levels are achieved. We therefore propose R-2HG-independent oncogenic functions of mutant IDH1 that may need to be targeted in addition to R-2HG production to exploit the full therapeutic potential of IDH1 inhibition.
Affiliation:
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
Citation:
Enantiomer-specific and paracrine leukemogenicity of mutant IDH metabolite 2-hydroxyglutarate. 2016, 30 (8):1708-15 Leukemia
Journal:
Leukemia
Issue Date:
Aug-2016
URI:
http://hdl.handle.net/10033/621098
DOI:
10.1038/leu.2016.71
PubMed ID:
27063596
Type:
Article
Language:
en
ISSN:
1476-5551
Appears in Collections:
publications of the research group genomeanalytics (GMAK)

Full metadata record

DC FieldValue Language
dc.contributor.authorChaturvedi, Aen
dc.contributor.authorAraujo Cruz, M Men
dc.contributor.authorJyotsana, Nen
dc.contributor.authorSharma, Aen
dc.contributor.authorGoparaju, Ren
dc.contributor.authorSchwarzer, Aen
dc.contributor.authorGörlich, Ken
dc.contributor.authorSchottmann, Ren
dc.contributor.authorStruys, E Aen
dc.contributor.authorJansen, E Een
dc.contributor.authorRohde, Cen
dc.contributor.authorMüller-Tidow, Cen
dc.contributor.authorGeffers, R.en
dc.contributor.authorGöhring, Gen
dc.contributor.authorGanser, Aen
dc.contributor.authorThol, Fen
dc.contributor.authorHeuser, Men
dc.date.accessioned2017-09-08T09:28:30Z-
dc.date.available2017-09-08T09:28:30Z-
dc.date.issued2016-08-
dc.identifier.citationEnantiomer-specific and paracrine leukemogenicity of mutant IDH metabolite 2-hydroxyglutarate. 2016, 30 (8):1708-15 Leukemiaen
dc.identifier.issn1476-5551-
dc.identifier.pmid27063596-
dc.identifier.doi10.1038/leu.2016.71-
dc.identifier.urihttp://hdl.handle.net/10033/621098-
dc.description.abstractCanonical mutations in IDH1 and IDH2 produce high levels of the R-enantiomer of 2-hydroxyglutarate (R-2HG), which is a competitive inhibitor of α-ketoglutarate (αKG)-dependent enzymes and a putative oncometabolite. Mutant IDH1 collaborates with HoxA9 to induce monocytic leukemia in vivo. We used two mouse models and a patient-derived acute myeloid leukemia xenotransplantation (PDX) model to evaluate the in vivo transforming potential of R-2HG, S-2HG and αKG independent of the mutant IDH1 protein. We show that R-2HG, but not S-2HG or αKG, is an oncometabolite in vivo that does not require the mutant IDH1 protein to induce hyperleukocytosis and to accelerate the onset of murine and human leukemia. Thus, circulating R-2HG acts in a paracrine manner and can drive the expansion of many different leukemic and preleukemic clones that may express wild-type IDH1, and therefore can be a driver of clonal evolution and diversity. In addition, we show that the mutant IDH1 protein is a stronger oncogene than R-2HG alone when comparable intracellular R-2HG levels are achieved. We therefore propose R-2HG-independent oncogenic functions of mutant IDH1 that may need to be targeted in addition to R-2HG production to exploit the full therapeutic potential of IDH1 inhibition.en
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject.meshAnimalsen
dc.subject.meshClone Cellsen
dc.subject.meshGlutaratesen
dc.subject.meshHeterograftsen
dc.subject.meshHomeodomain Proteinsen
dc.subject.meshHumansen
dc.subject.meshIsocitrate Dehydrogenaseen
dc.subject.meshIsomerismen
dc.subject.meshKetoglutaric Acidsen
dc.subject.meshLeukemia, Myeloid, Acuteen
dc.subject.meshMiceen
dc.subject.meshMutationen
dc.subject.meshOncogenesen
dc.subject.meshParacrine Communicationen
dc.titleEnantiomer-specific and paracrine leukemogenicity of mutant IDH metabolite 2-hydroxyglutarate.en
dc.typeArticleen
dc.contributor.departmentHelmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.en
dc.identifier.journalLeukemiaen

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