R-2-hydroxyglutarate attenuates aerobic glycolysis in leukemia by targeting the FTO/m6A/PFKP/LDHB axis

Ying Qing, Lei Dong, Lei Gao, Chenying Li, Yangchan Li, Li Han, Emily Prince, Brandon Tan, Xiaolan Deng, Collin Wetzel, Chao Shen, Min Gao, Zhenhua Chen, Wei Li, Bin Zhang, Daniel Braas, Johanna ten Hoeve, Gerardo Javier Sanchez, Huiying Chen, Lai N. ChanChun Wei Chen, David Ann, Lei Jiang, Markus Müschen, Guido Marcucci, David R. Plas, Zejuan Li, Rui Su, Jianjun Chen

Research output: Contribution to journalArticle

Abstract

R-2-hydroxyglutarate (R-2HG), a metabolite produced by mutant isocitrate dehydrogenases (IDHs), was recently reported to exhibit anti-tumor activity. However, its effect on cancer metabolism remains largely elusive. Here we show that R-2HG effectively attenuates aerobic glycolysis, a hallmark of cancer metabolism, in (R-2HG-sensitive) leukemia cells. Mechanistically, R-2HG abrogates fat-mass- and obesity-associated protein (FTO)/N6-methyladenosine (m6A)/YTH N6-methyladenosine RNA binding protein 2 (YTHDF2)-mediated post-transcriptional upregulation of phosphofructokinase platelet (PFKP) and lactate dehydrogenase B (LDHB) (two critical glycolytic genes) expression and thereby suppresses aerobic glycolysis. Knockdown of FTO, PFKP, or LDHB recapitulates R-2HG-induced glycolytic inhibition in (R-2HG-sensitive) leukemia cells, but not in normal CD34+ hematopoietic stem/progenitor cells, and inhibits leukemogenesis in vivo; conversely, their overexpression reverses R-2HG-induced effects. R-2HG also suppresses glycolysis and downregulates FTO/PFKP/LDHB expression in human primary IDH-wild-type acute myeloid leukemia (AML) cells, demonstrating the clinical relevance. Collectively, our study reveals previously unrecognized effects of R-2HG and RNA modification on aerobic glycolysis in leukemia, highlighting the therapeutic potential of targeting cancer epitranscriptomics and metabolism. Qing et al. demonstrate that R-2HG, a metabolite produced by mutant IDH, significantly suppresses aerobic glycolysis in sensitive (IDH-wild-type) leukemia cells, but not in normal hematopoietic stem/progenitor cells. R-2HG exerts glycolytic inhibitory effects by targeting the FTO/m6A/YTHDF2 signaling to downregulate PFKP and LDHB expression, contributing to its overall anti-tumor activity.

Original languageEnglish (US)
Pages (from-to)922-939.e9
JournalMolecular Cell
Volume81
Issue number5
DOIs
StatePublished - Mar 4 2021

Keywords

  • FTO
  • LDHB
  • N-methyladenosine (mA) modification
  • PFKP
  • R-2HG
  • RNA stability
  • YTHDF2
  • cancer metabolism
  • glycolysis
  • leukemia

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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