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

Abstract

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 CEBPα-induced fatty acid β-oxidation of IDH1 mutant cells. While IDH1 mutant inhibitor reduced 2-HG oncometabolite and CEBPα 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-γ coactivator-1 PGC1α 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.

Activation of Vitamin D Receptor Pathway Enhances Differentiating Capacity in Acute Myeloid Leukemia with Isocitrate Dehydrogenase Mutations

“…Lentiviral infection was carried out as previously described [13]. Briefly, each construct (6 µg) was co-transfected using lipofectamine 2000 with p8.1 (4 µg) and pVSV-G (2 µg) (providing packaging and envelope proteins) into 293T cells to produce lentiviral particles.…”

“…Proteins were analyzed by Western Blot as previously described [13]. List of antibodies used in this work: anti-CEBPα (2841, CST, 1:1000), anti-CEBPβ (sc-150, Santa Cruz, 1:1000), anti-GAPDH (5174, CST, 1:10,000), anti-HSP90 (4874, CST, 1:1000), anti-IDH2 (ab55271, Abcam, 1:1000), anti-IDH2-R172K (ab264052, Abcam, 1:1000), anti-RARα (gifted by Prof. Hugues de Thé), anti-RXRα (3085, CST), anti-Actinin (3134, CST, 1:10,000), anti-VDR (12550, CST).…”

Autophagy a Close Relative of AML Biology

“…Several key proteins are involved in the autophagic process: for example, ULK1 (Unc-51 like autophagy activating kinase 1), FIP200/RB1CC1 (focal adhesion kinase family interacting protein of 200 kD/RB1 inducible coiled-coil 1), BECLIN1, VPS34, and ATG14 are involved in the phagophore formation, while ATG5, ATG7, ATG12, and LC3-II (microtubule-associated protein 1 light chain 3) regulate the autophagosome formation [ 5 ]. In addition to bulk degradation, autophagy can trigger the selective elimination of impaired or extra organelles, such as mitochondria, the powerhouse of the cell, recently shown to be a key organelle in AML therapeutic resistance [ 6 , 7 ]. This selective autophagy, called mitophagy, allows the specific clearance of damaged, dysfunctional, or superfluous mitochondria, contributing to the maintenance of a functional pool of mitochondria.…”

Novel CD123 polyaptamer hydrogel edited by Cas9/sgRNA for AML-targeted therapy

“…Targeted therapy, one of the most effective methods for cancer treatment, is a promising method for AML treatment. Targeted therapy could deliver drugs and inhibit AML cells selectively but not to their normal counterparts (Stuani et al, 2021 ). The alpha chain of interleukin 3 receptor (IL3R-α), designated as CD123, has been validated a mainstream target for AML.…”