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.
While transcription factor C/AAT-enhancer binding protein a (C/EBPa) is critical for normal and leukemic differentiation, its role on cell and metabolic homeostasis is largely unknown in cancer. Here, multi-omics analyses uncovered a coordinated activation of C/EBPa and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism in vivo and in patients with FLT3-mutant acute myeloid leukemia (AML). Mechanistically, C/EBPa regulated FASN-SCD axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPa inactivation decreased mono-unsaturated FA incorporation to membrane phospholipids through SCD downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress that was exploited by combining FLT3 and glutathione peroxidase 4 inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of FLT3-mutant AML cells. Altogether, our study reveals a C/EBPa function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of FLT3-mutant AML to ferroptosis with promising therapeutic application
Relapses and resistance to therapeutic agents are major barriers in the treatment of acute myeloid leukemia (AML) patients. These unfavorable outcomes emphasize the need for new strategies targeting drug-resistant cells. As IDH mutations are present in the preleukemic stem cells and systematically conserved at relapse, targeting IDH mutant cells could be essential to achieve a long-term remission in the IDH mutant AML subgroup. Here, using a panel of human AML cell lines and primary AML patient specimens harboring IDH mutations, we showed that the production of an oncometabolite (R)-2-HG by IDH mutant enzymes induces vitamin D receptor-related transcriptional changes, priming these AML cells to differentiate with pharmacological doses of ATRA and/or VD. This activation occurs in a CEBPα-dependent manner. Accordingly, our findings illuminate potent and cooperative effects of IDH mutations and the vitamin D receptor pathway on differentiation in AML, revealing a novel therapeutic approach easily transferable/immediately applicable to this subgroup of AML patients.
Phone: +33 582 74 16 32 51 52 Running Title: IDH and OxPHOS inhibitors 53 54 55 3 Isocitrate dehydrogenases (IDH) are involved in redox control and central metabolism. 56Mutations in IDH induce epigenetic and transcriptional reprogramming, differentiation 57 bias, BCL-2 dependence and susceptibility to mitochondrial inhibitors in cancer cells. 58Here we show that high sensitivity to mitochondrial oxidative phosphorylation 59 (OxPHOS) inhibitors is due to an enhanced mitochondrial oxidative metabolism in cell 60 lines, PDX and patients with acute myeloid leukemia (AML) harboring IDH mutation. 61Along with an increase in TCA cycle intermediates, this AML-specific metabolic 62 behavior mechanistically occurs through the increase in methylation-driven CEBPα-63 and CPT1a-induced fatty acid oxidation, electron transport chain complex I activity and 64 mitochondrial respiration in IDH1 mutant AML. Furthermore, an IDH mutant 65 inhibitor that significantly and systematically reduces 2-HG oncometabolite transiently 66 reverses mitochondrial FAO and OxPHOS gene signature and activities in patients who 67 responded to the treatment and achieved the remission. However, at relapse or in 68 patients who did not respond, IDH mutant inhibitor failed to block these mitochondrial 69properties. Accordingly, OxPHOS inhibitors such as IACS-010759 improve anti-AML 70
efficacy of IDH mutant inhibitors alone and in combination with chemotherapy in vivo. 71This work provides a scientific rationale for combinatory mitochondrial-targeted 72 therapies to treat IDH mutant-positive AML patients, especially those unresponsive to 73 or relapsing from IDH mutant-specific inhibitors. 74 75 76 4Changes in intermediary and energy metabolism provide the flexibility for cancer cells to 77 adapt their metabolism to meet energetic and biosynthetic requirements for proliferation [1][2][3][4] . 78Manipulating glycolysis, glutaminolysis, fatty acid β-oxidation (FAO) or oxidative 79 phosphorylation (OxPHOS) markedly reduces cell growth in vitro and in vivo and sensitizes 80 acute myeloid leukemia (AML) cells to chemotherapeutic drugs [5][6][7][8][9][10][11][12][13] . The importance of the 81 metabolic reprogramming in this disease is further illustrated by recurrent mutations in genes 82 of two crucial metabolic enzymes, isocitrate dehydrogenases (IDH) 1 and 2, present in more 83 than 15% of AML patients [14][15][16][17] . 84The impact of IDH mutation and the related accumulation of the oncometabolite (R)-2-85 hydroxyglutarate (2-HG) have been well documented in leukemic transformation and AML 86 biology 18-28 . As IDH mutations are early events in oncogenesis and are systematically 87 conserved at relapse 29-31 , IDH1/2 mutated (IDHm) enzymes represent attractive therapeutic 88 targets and small molecules specifically inhibiting the mutated forms of these enzymes have 89 been developed and recently approved by the FDA 32-41 . Both the IDH2m-and IDH1m-90 inhibitors promote differentiation and reduce methylation levels as well as significantly 91 decrease 2...
The development of resistance to conventional and targeted therapy represents a major clinical barrier in treatment of acute myeloid leukemia (AML). We show that the resistance to cytarabine (AraC) and its associated mitochondrial phenotype were reversed by genetic silencing or pharmacological inhibition of BCL2 in a caspase-dependent manner. BCL2-inhibitor venetoclax (VEN) enhancement of AraC efficacy was independent of differentiation phenotype, a characteristic of response to another combination of VEN with hypomethylating agents (HMA). Furthermore, transcriptional profiles of patients with low response to VEN+AraC mirrored those of low responders to VEN+HMA in clinical trials. OxPHOS was found to be a patient stratification marker predictive of effective response to VEN+AraC but not to VEN+AZA. Importantly, whereas three cell subpopulations specifically emerged in VEN+AraC residual disease and were characterized by distinct developmental and transcriptional programs largely driven by MITF, E2F4 and p53 regulons, they each encoded proteins involved in assembly of NADH dehydrogenase complex. Notably, treatment of VEN+AraC-persisting AML cells with an ETCI inhibitor significantly increased the time-to-relapse in vivo. These findings provide the scientific rationale for new clinical trials of VEN+AraC combinations, especially in patients relapsing or non-responsive to chemotherapy, or after failure of frontline VEN+HMA regimen
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