Characterization of Mutations in the Mitochondrial Encoded Electron Transport Chain Complexes in Acute Myeloid Leukemia

Abstract

Acute Myeloid Leukemia is a devastating and heterogeneous, hematological malignancy characterized by the uncontrolled proliferation of undifferentiated myeloid progenitor cells—blasts. Mutations in certain mitochondrial proteins, such as IDH2 have been shown to contribute to leukemogenesis. However, the role of mutations in mitochondrial-encoded Electron Transport Chain (ETC) genes have thus far not been well elucidated in AML. Here, we use TCGA data to characterize mutations in the ETC genes and their association with clinical outcomes in AML. We found that mitochondrial ETC mutations—in Complex I, III, IV and/or V (ATP Synthase)—were present in 8% of patients with AML and were significantly more frequent in older patients. Patients with ETC mutations had worse overall survival than ETC wild type patients (OS: 9.3 vs 20.1 months; p-value: 0.007). Additionally, mutations in either or both Complex I and IV were associated with TP53 mutations (p-value: 0.009), and among TP53 mutated patients, mutations in either or both Complex I and IV were significantly associated with worse overall survival (OS: 0.85 vs 9.4 months; p-value: 0.008). Elucidation of the mechanisms by which ETC mutations contribute to AML pathogenesis and progression would facilitate the development of novel therapeutic targets.

Mitochondrial DNA Mutation Analysis in Breast Cancer: Shifting From Germline Heteroplasmy Toward Homoplasmy in Tumors

“…Overall survival analysis showed no differences among patients carrying a high versus low mtDNA mutational burden in tumors, which is in contrast with the data reported in breast cancer (28). A high mtDNA mutational burden has been associated with a worse outcome in pulmonary adenocarcinoma, acute myeloid leukemia, and pancreatic ductal adenocarcinoma (18,111,112); the opposite was observed in oral squamous cell carcinoma, and even acute myeloid leukemia, and breast cancer (28,113,114). We cannot exclude potential bias due to the nature of the studied mutations, the clinical characteristics of the patients included, or the ethnic/genetic background of the populations studied.…”

“…Our small sample size and potential population stratification, since all patients were recruited in Mexico City, might also bias our results. As well, we cannot ignore the fact that other alterations, such as the mtDNA-CN (suggested as a potential prognostic biomarker for breast cancer), mito epigenetic processes, and nuclear genes that are involved in the mitochondrial biogenesis, may be clinically relevant (18,71,115,116). Thus, studies are necessary for larger cohorts of patients to determine the significance of the mtDNA mutational burden as a biomarker in breast cancer.…”

“…The relative abundance of certain de novo mutations might be pathogenic, although the heteroplasmic threshold effect and the molecular mechanisms underlying the mutation selection during disease development have not yet been established (15). However, the association among several mtDNA germline variants and a broad spectrum of human malignancies has been widely documented (16)(17)(18). For instance, the T16189C (D-Loop) and G10398A (A114T at ND3 gene) germline variants have been commonly associated with an increased risk of cancer (17,(19)(20)(21).…”

Immunometabolism: A new target for improving cancer immunotherapy

“…Because Warburg also observed increased aerobic glycolysis in normal proliferating cells and noted that it was reversible under normal conditions, he postulated that aerobic glycolysis was a consequence of irreversible damage to respiration in tumors (Warburg et al, 1924). Although later studies found mutations in some mitochondrial DNA-encoded ETC genes and genomic DNA-encoded genes of the TCA cycle (Baysal et al, 2000;Ward et al, 2010;Wu, Akhtari, & Alachkar, 2018), damaged respiration as an intrinsic property or "origin" of cancer is not established ( Ju et al, 2014;Stewart et al, 2015). In addition, hypoxia has long been known to stimulate glycolytic metabolism (Semenza, 2012).…”

Utilizing Synergistic Potential of Mitochondria-Targeting Drugs for Leukemia Therapy

“…This has been cited as a justification for the development mitochondria-targeting compounds (14,15). Drugs targeting many other aspects of mitochondrial biology, such as the generation of reactive oxygen species, the electron transport chain, or the mitochondrial permeability transition pore have also been shown to kill tumor cells (16)(17)(18)(19)(20)(21)(22). "Mitocan" has been proposed as a generalized term for Abbreviations:…”