Ogdh Is a Genetic Vulnerability and Therapeutic Target in Acute Myeloid Leukemia

Tricarboxylic acid (TCA) cycle metabolites play a key part in cell bioenergetics, generating products for downstream ATP synthesis. However, beyond their role in central carbon metabolism, these metabolites also modulate processes such as cell proliferation, growth, and differentiation through regulation of numerous chromatin modifying enzymes and transcriptional programs. Therapeutic modulation of dysregulated metabolism has emerged as a successful strategy for acute myeloid leukemia (AML) harboring oncogenic isocitrate dehydrogenase (IDH) mutations. Inhibition of mutant IDH results in terminal myeloid differentiation of leukemic blasts and led to FDA-approval of IDH1 and IDH2 inhibitors in AML. However, there are currently no metabolism-directed therapies approved for AML lacking IDH mutations, which represents the majority of AML patients.

Our prior work demonstrates that the tumor suppressive output of p53-- itself mutated in ~10% of AML cases, associated with complex karyotypes and portending a particularly unfavorable prognosis-- is in part mediated through alpha-ketoglutarate (aKG) accumulation. We therefore investigated whether alternative modes of aKG upregulation could produce anti-leukemic effects in AML systems. Here, we describe the identification of 2-oxoglutarate dehydrogenase (OGDH), a subunit of the aKG dehydrogenase complex that participates in the TCA cycle to convert aKG to succinyl CoA, as a metabolic vulnerability with specificity for AML. Genetic inhibition of this enzyme hinders leukemia cell survival and progression both in vitro and in vivo across different genotypic models of AML, including those harboring p53 mutations. We show that OGDH depletion is sufficient to increase cellular aKG levels and drive differentiation phenotypes in AML cells through regulation of cell fate-determining transcription factors. Metabolically, OGDH depletion ablates the spare respiratory capacity of AML cells, but only minimally compromises basal cellular respiration. Specific to AML, the loss of OGDH inhibits nucleotide production, with cells demonstrating globally reduced pyrimidine biosynthesis and a distinct block in the purine biosynthesis pathway. These results emphasize the importance of nutrient stressors in the maintenance and cell fate decisions of AML.

To estimate the putative toxicities of targeting central carbon metabolism, we generated a systemic, inducible murine model of OGDH knockdown designed to estimate the effects of a potent, fully on-target inhibitor. While gastrointestinal toxicity is appreciated upon OGDH depletion, the hematopoietic compartment is largely preserved at early assessments, in stark contrast to the robust anti-leukemic effects observed at matching timepoints. Mice demonstrate only mild lymphopenia and are without evidence of dysfunctional erythropoiesis or thrombopoiesis. We do observe a modest effect on the proliferation and clonogenicity of bone marrow cells ex vivo, but these effects appear reversible upon restoration of OGDH activity. Furthermore, nucleoside pools in bone marrow progenitor cells remain predominantly intact.

Taken together, these results identify and validate OGDH as a dependency and therapeutic target in AML, with the metabolic effects of its inhibition converging on cell fate pathways. Moreover, limited and/or reversible toxicities from targeting the TCA cycle in normal tissues suggest a potential therapeutic window for pharmacologic intervention.

Millman:Regeneron Pharmaceuticals: Other: Employment (spouse); Equity holder (spouse). Chen:Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Lowe:Algen: Other: Intellectual Property Rights; Petra Pharma Corporation: Other: Ownership / Equity Interests; Provision of Services; PMV Pharma: Other: Ownership / Equity Interests; Provision of Services; Blueprint Medicines: Other: Ownership / Equity Interests; Provision of Services; Constellation Pharmaceuticals: Other: Ownership / Equity Interests; Provision of Services; Eli Lilly and Company: Other: Provision of Services; Faeth Therapeutics, Inc: Other: Ownership / Equity Interests; Provision of Services (uncompensated); Geras Bio Inc: Other: Ownership / Equity Interests; Provision of Services (uncompensated); Mirimus: Other: Ownership / Equity Interests; Provision of Services; Oric Pharmaceuticals: Other: Ownership / Equity Interests; Provision of Services.