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  2. α-Ketoglutarate-Mediated DNA Demethylation Sustains T-Acute Lymphoblastic Leukemia upon TCA Cycle Targeting

α-Ketoglutarate-Mediated DNA Demethylation Sustains T-Acute Lymphoblastic Leukemia upon TCA Cycle Targeting

  • Cancers (Basel). 2022 Jun 16;14(12):2983. doi: 10.3390/cancers14122983.
Yanwu Wang 1 2 Ning Shen 2 3 Gervase Spurlin 2 Sovannarith Korm 2 Sarah Huang 2 Nicole M Anderson 2 Leah N Huiting 2 Hudan Liu 4 5 Hui Feng 2 3
Affiliations

Affiliations

  • 1 Taikang Medical School (School of Basic Medical Science), Wuhan University, Wuhan 430071, China.
  • 2 Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA.
  • 3 Department of Medicine, Section of Hematology and Medical Oncology, Boston University School of Medicine, Boston, MA 02118, USA.
  • 4 Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
  • 5 Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan 430071, China.
Abstract

Despite the development of metabolism-based therapy for a variety of malignancies, resistance to single-agent treatment is common due to the metabolic plasticity of Cancer cells. Improved understanding of how malignant cells rewire metabolic pathways can guide the rational selection of combination therapy to circumvent drug resistance. Here, we show that human T-ALL cells shift their metabolism from oxidative decarboxylation to reductive carboxylation when the TCA cycle is disrupted. The α-ketoglutarate dehydrogenase complex (KGDHC) in the TCA cycle regulates oxidative decarboxylation by converting α-ketoglutarate (α-KG) to succinyl-CoA, while isocitrate dehydrogenase (IDH) 1 and 2 govern reductive carboxylation. Metabolomics flux analysis of T-ALL reveals enhanced reductive carboxylation upon genetic depletion of the E2 subunit of KGDHC, dihydrolipoamide-succinyl transferase (DLST), mimicking pharmacological inhibition of the complex. Mechanistically, KGDHC dysfunction causes increased demethylation of nuclear DNA by α-KG-dependent dioxygenases (e.g., TET demethylases), leading to increased production of both IDH1 and 2. Consequently, dual pharmacologic inhibition of the TCA cycle and TET demethylases demonstrates additive efficacy in reducing the tumor burden in zebrafish xenografts. These findings provide mechanistic insights into how T-ALL develops resistance to drugs targeting the TCA cycle and therapeutic strategies to overcome this resistance.

Keywords

DNA demethylation; T-cell acute lymphoblastic leukemia; TCA cycle; oxidative phosphorylation; reductive carboxylation; α-ketoglutarate.

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