Integrated bioinformatic analysis of mitochondrial metabolism-related genes in acute myeloid leukemia

Abstract

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.

Monocytic Differentiation in Acute Myeloid Leukemia Cells: Diagnostic Criteria, Biological Heterogeneity, Mitochondrial Metabolism, Resistance to and Induction by Targeted Therapies

“…High expression of these genes was associated with the concomitant expression of unfavorable metabolic regulatory genes (see Section 3 ). Another bioinformatical study based on bone marrow gene expression profiles classified patients into favorable and adverse prognostic subsets based on their mitochondrial metabolic gene profile [ 71 ], and this study also suggested that high-risk patients showed a higher infiltration of immunocompetent cells and, especially, M2 macrophages, γδ T cells, MDSCs and Treg cells.…”

“…As outlined above, mitochondria-related reprogramming is important in AML, and two recent studies therefore investigated the possible prognostic impact of mitochondria-related genes for patients receiving conventional intensive antileukemic therapy [ 70 , 71 ]. The first study was based on an analysis of 149 patients, and they constructed a prognostic model based on the expression/RNA levels of the following four metabolic genes (information from the Gene database, accessed on 6 October 2023) [ 70 ]: 4-hydroxyphenylpyruvate dioxygenase like ( HPDL , chromosome 1).…”

“…An alternative prognostic model also based on mitochondrial metabolic markers has been described [ 71 ]. Its development was based on several public transcriptome databases; 31 mitochondrial metabolism-related genes were first selected, and finally, a prognostic model was constructed based on five genes that differed from the four genes listed above [ 70 ] (information from the Gene database, accessed 6 October 2023): Enoyl-CoA hydratase, short chain 1 ( ECHS1 , chromosome 10).…”

“…To conclude, these two studies show that mitochondrial proteins encoded by nuclear DNA are important for the sensitivity of AML cells to conventional intensive chemotherapy, and these key regulators are involved in glucose, fatty acid and amino acid metabolism [ 70 , 71 ]. Additional analyses in both studies suggested that high-risk patients differed from low-risk patients with regards to the infiltration of immunocompetent cells, and high mitochondrial-related gene risk scores were thus possibly associated with an immunosuppressive microenvironment [ 70 , 71 ].…”

High Mitochondrial Protein Expression as a Potential Predictor of Relapse Risk in Acute Myeloid Leukemia Patients with the Monocytic FAB Subtypes M4 and M5

“…First, monocytic differentiation reflected by the FAB classification is associated with resistance to venetoclax-based (i.e., a BCL-2 inhibitor), and this resistance seems to be due to decreased functional importance of BCL-2 and thereby altered regulation of apoptosis and mitochondrial energy metabolism in monocytic AML cells, including leukemic stem cells [ 30 , 31 , 50 , 77 ]. Second, differential expression of mitochondria-related genes is important for chemoresistance and seems to have an independent prognostic impact in AML [ 78 ]. Third, a subset of AML patients show mutations in genes that encode proteins in the electron transport complexes (Complex I/III/IV, ATP synthase), and mutations in the mitochondrial NADH dehydrogenase subunit 4 (a component of Complex I) seem to have a prognostic impact in adult AML [ 79 , 80 ].…”