title: Enantiomer-specific and paracrine leukemogenicity of mutant IDH metabolite 2-hydroxyglutarate.
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.
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Chaturvedi
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: M M
authors.initials: MM
authors.lastname: Araujo Cruz
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Jyotsana
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Goparaju
authors.affiliation: Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Schwarzer
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Görlich
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Schottmann
authors.affiliation: Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: E A
authors.initials: EA
authors.lastname: Struys
authors.affiliation: Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: E E
authors.initials: EE
authors.lastname: Jansen
authors.affiliation: Department of Hematology and Oncology, University of Halle, Halle, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Rohde
authors.affiliation: Department of Hematology and Oncology, University of Halle, Halle, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Müller-Tidow
authors.affiliation: Genome Analytics Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Geffers
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Göhring
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Ganser
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Thol
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Heuser
mesh_terms: D000818:Animals; D002999:Clone Cells / Q000473:pathology; D005977:Glutarates; D064593:Heterografts; D018398:Homeodomain Proteins / Q000502:physiology; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000502:physiology; D007536:Isomerism; D007656:Ketoglutaric Acids; D015470:Leukemia, Myeloid, Acute / Q000209:etiology* / Q000473:pathology; D051379:Mice; D009154:Mutation; D009857:Oncogenes; D019899:Paracrine Communication / Q000502:physiology*
chemical_list: D005977:Glutarates; D018398:Homeodomain Proteins; D007656:Ketoglutaric Acids; C097899:homeobox protein HOXA9; C019417:alpha-hydroxyglutarate; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human