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 αKG-dependent enzymes and a putative oncometabolite. Mutant IDH1 collaborates with HoxA9 to induce monocytic leukemia in vivo. We employed two mouse models and a patient derived AML 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 fashion and can drive the expansion of many different leukemic and preleukemic clones that may express wildtype 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.

Vitamin C-induced epigenomic remodelling in IDH1 mutant acute myeloid leukaemia

“…In support of this notion, multiple reports have shown that the R -2-hydroxyglutarate initiates leukaemogenesis in a reversible manner. 3 , 4 AML patient genomes also demonstrate mutual exclusivity in mutations to IDH and TET2 ; and TET2 -mutant AMLs show an overlapping promoter hypermethylation signature with IDH1/2 -mutant AMLs. 5 Survival data associated with TET2 and IDH1/2 mutations in AML patients are inconsistent and no prognostic significance to these mutations has been conclusively established.…”

Epigenetic Regulators in the Development, Maintenance, and Therapeutic Targeting of Acute Myeloid Leukemia

“…These results suggest that similar to DNMT3A, IDH mutations may also need secondary mutations for initiation of frank malignancy in AML. Strikingly, the same group also demonstrated that in vivo injection of the oncometabolite 2-HG, could recapitulate most, but not all of the oncogenic effects of the IDH1 mutation ( 10 ). These interesting observations reinforced the role of 2-HG as an oncometabolite but also suggested that IDH1 may have additional oncogenic functions beyond its role in 2-HG accumulation.…”

The Time Has Come for Targeted Therapies for AML: Lights and Shadows

“…2-HG competitively inhibits the function of aKG-dependent oxygenases involved in DNA or histone demethylation, resulting in global DNA hypermethylation of regulatory genes and arrested myeloid differentiation. The mutation also increases reactive oxygen species (ROS) output and cell-cycle transition through the activation of MAPK (mitogen-activated protein kinase) signaling and the repression of cyclindependent kinase inhibitors Cdkn2a and Cdkn2b, resulting in metabolic changes leading to upregulation of NF-Kb and BCL-2 proteins [31][32][33][34][35][36].…”