Mitochondrial metabolism supports resistance to IDH mutant inhibitors in acute myeloid leukemia.

  • Quantitative Biology Unit
May 03, 2021 By:
  • Stuani L
  • Sabatier M
  • Saland E
  • Cognet G
  • Poupin N
  • Bosc C
  • Castelli FA
  • Gales L
  • Turtoi E
  • Montersino C
  • Farge T
  • Boet E
  • Broin N
  • Larrue C
  • Baran N
  • Cisse MY
  • Conti M
  • Loric S
  • Kaoma T
  • Hucteau A
  • Zavoriti A
  • Sahal A
  • Mouchel PL
  • Gotanegre M
  • Cassan C
  • Fernando L
  • Wang F
  • Hosseini M
  • Chu-Van E
  • Le Cam L
  • Carroll M
  • Selak MA
  • Vey N
  • Castellano R
  • Fenaille F
  • Turtoi A
  • Cazals G
  • Bories P
  • Gibon Y
  • Nicolay B
  • Ronseaux S
  • Marszalek JR
  • Takahashi K
  • DiNardo CD
  • Konopleva M
  • Pancaldi V
  • Collette Y
  • Bellvert F
  • Jourdan F
  • Linares LK
  • Recher C
  • Portais JC
  • Sarry JE.

Mutations in IDH induce epigenetic and transcriptional reprogramming, differentiation bias, and susceptibility to mitochondrial inhibitors in cancer cells. Here, we first show that cell lines, PDXs, and patients with acute myeloid leukemia (AML) harboring an IDH mutation displayed an enhanced mitochondrial oxidative metabolism. Along with an increase in TCA cycle intermediates, this AML-specific metabolic behavior mechanistically occurred through the increase in electron transport chain complex I activity, mitochondrial respiration, and methylation-driven CEBPalpha-induced fatty acid beta-oxidation of IDH1 mutant cells. While IDH1 mutant inhibitor reduced 2-HG oncometabolite and CEBPalpha methylation, it failed to reverse FAO and OxPHOS. These mitochondrial activities were maintained through the inhibition of Akt and enhanced activation of peroxisome proliferator-activated receptor-gamma coactivator-1 PGC1alpha upon IDH1 mutant inhibitor. Accordingly, OxPHOS inhibitors improved anti-AML efficacy of IDH mutant inhibitors in vivo. This work provides a scientific rationale for combinatory mitochondrial-targeted therapies to treat IDH mutant AML patients, especially those unresponsive to or relapsing from IDH mutant inhibitors.

2021 May. J Exp Med.218(5).
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