Dataset Information

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.

SUBMITTER: Stuani L

PROVIDER: S-EPMC7995203 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Stuani Lucille L Sabatier Marie M Saland Estelle E Cognet Guillaume G Poupin Nathalie N Bosc Claudie C Castelli Florence A FA Gales Lara L Turtoi Evgenia E Montersino Camille C Farge Thomas T Boet Emeline E Broin Nicolas N Larrue Clément C Baran Natalia N Cissé Madi Y MY Conti Marc M Loric Sylvain S Kaoma Tony T Hucteau Alexis A Zavoriti Aliki A Sahal Ambrine A Mouchel Pierre-Luc PL Gotanègre Mathilde M Cassan Cédric C Fernando Laurent L Wang Feng F Hosseini Mohsen M Chu-Van Emeline E Le Cam Laurent L Carroll Martin M Selak Mary A MA Vey Norbert N Castellano Rémy R Fenaille François F Turtoi Andrei A Cazals Guillaume G Bories Pierre P Gibon Yves Y Nicolay Brandon B Ronseaux Sébastien S Marszalek Joseph R JR Takahashi Koichi K DiNardo Courtney D CD Konopleva Marina M Pancaldi Véra V Collette Yves Y Bellvert Floriant F Jourdan Fabien F Linares Laetitia K LK Récher Christian C Portais Jean-Charles JC Sarry Jean-Emmanuel JE

The Journal of experimental medicine 20210501 5

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 ...[more]

PMID: 33760042

Similar Datasets

Project description:BackgroundAcute myeloid leukemia (AML) is a common hematologic malignancy characterized by poor prognoses and high recurrence rates. Mitochondrial metabolism has been increasingly recognized to be crucial in tumor progression and treatment resistance. The purpose of this study was to examined the role of mitochondrial metabolism in the immune regulation and prognosis of AML.MethodsIn this study, mutation status of 31 mitochondrial metabolism-related genes (MMRGs) in AML were analyzed. Based on the expression of 31 MMRGs, mitochondrial metabolism scores (MMs) were calculated by single sample gene set enrichment analysis. Differential analysis and weighted co-expression network analysis were performed to identify module MMRGs. Next, univariate Cox regression and the least absolute and selection operator regression were used to select prognosis-associated MMRGs. A prognosis model was then constructed using multivariate Cox regression to calculate risk score. We validated the expression of key MMRGs in clinical specimens using immunohistochemistry (IHC). Then differential analysis was performed to identify differentially expressed genes (DEGs) between high- and low-risk groups. Functional enrichment, interaction networks, drug sensitivity, immune microenvironment, and immunotherapy analyses were also performed to explore the characteristic of DEGs.ResultsGiven the association of MMs with prognosis of AML patients, a prognosis model was constructed based on 5 MMRGs, which could accurately distinguish high-risk patients from low-risk patients in both training and validation datasets. IHC results showed that MMRGs were highly expressed in AML samples compared to normal samples. Additionally, the 38 DEGs were mainly related to mitochondrial metabolism, immune signaling, and multiple drug resistance pathways. In addition, high-risk patients with more immune-cell infiltration had higher Tumor Immune Dysfunction and Exclusion scores, indicating poor immunotherapy response. mRNA-drug interactions and drug sensitivity analyses were performed to explore potential druggable hub genes. Furthermore, we combined risk score with age and gender to construct a prognosis model, which could predict the prognosis of AML patients.ConclusionOur study provided a prognostic predictor for AML patients and revealed that mitochondrial metabolism is associated with immune regulation and drug resistant in AML, providing vital clues for immunotherapies.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets