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

Background: Acute Myeloid Leukemia (AML) is a devastating and heterogeneous, hematological malignancy characterized by uncontrolled proliferation of undifferentiated myeloid progenitor cells-blasts. AML cells are highly oxidized compared to healthy hematopoietic stem cells; thus, mechanisms contributing to this oxidation state represent an opportunity for targeted therapy. Oxidative phosphorylation (OXPHOS) is a key intracellular process where electrons are passed through the Electron Transport Chain (ETC) to produce the cellular fuel-ATP; however, during this process electrons leak from certain complexes of the ETC to form superoxide anions-free radicals that bind to iron-sulfur cores of important enzymes and inactivate them, inhibiting pivotal cellular pathways. Mutations or defects in the mitochondrial encoded ETC complexes (I, III, IV and V) could have significant effects on the metabolic balance of the mitochondria. While mitochondrial DNA (mtDNA) mutations have been previously reported in hematologic malignancies, including AML, mutations in the ETC genes encoded by the mitochondria have not been fully characterized.

Methods: We analyzed molecular and clinical patient data retrieved from the Cancer Genome Atlas (TCGA) dataset for 200 patients with AML. We assessed the association between the presence of mutations in the mitochondrial encoded ETC with the clinical and molecular characteristics of patients with AML, using the Mann-Whitney U or Fisher Exact test. Additionally, we generated Kaplan-Meier survival curves to assess the association between presence of mutations in mitochondrial encoded ETC genes and clinical outcome. For multivariable survival analysis, we used the Cox Proportional Hazards Model to adjust for other risk factors. All statistical analysis was done using STATE 12.0 SE.

Results: We found that mtDNA ETC mutations were present in 8% of patients with AML (16 of 200) with most of the mutations present in Complex IV (9 of 16 patients: 56.3%). MtDNA ETC mutations were significantly more frequent in older patients (%: 81.2 vs 18.8; p-value: 0.003), in patients with M0 FAB classification (%: 26.7 vs 8.22; p-value: 0.04) and in patients with poor molecular risk (%: 50 vs 23.4; p-value: 0.035). The median age of patients with Complex IV mutations was higher than that in patients without the mutations (median: 72 vs 57; p-value: 0.009), and these mutations were more frequent in patients with M0 FAB classification (%: 33.3 vs 8.47; p-value: 0.04). TP53 mutations were significantly more frequent in patients with mtDNA ETC gene mutations (%: 31.3 vs 5.95; p-value: 0.004). Similarly, after complex stratification, mutations in TP53 were more frequent in patients with Complex IV mutations (%: 33.3 vs 6.81; p-value: 0.026) and in patients with mutations in either or both Complex I and IV (%: 33.3 vs 6.38; p-value: 0.009).

Patients with mtDNA ETC gene mutations had worse overall survival than wild type patients (median: 9.3 vs 20.1 months; p-value: 0.007). Comparably, after excluding M3 APL patients (due to their different treatment and improved overall survival), patients with mtDNA ETC mutations still had worse overall survival than patients carrying the mtDNA ETC wild type (median: 9.3 vs 15.8; p-value: 0.0139). Patients with Complex I mutations had worse overall survival (median: 5.85 vs 18.5 months; p-value: 0.009) than those without Complex I mutations. Likewise, patients with Complex IV mutations also had worse overall survival than those without Complex IV mutations (median: 7.0 vs 18.5 months; p-value: 0.047). In patients who did not receive transplant as part of their treatment regimen, presence of mtDNA ETC gene mutations were significantly associated with worse overall survival (median: 4.35 vs 9.9 months; p-value: 0.0123). And among TP53 mutated patients, mutations in either or both Complex I and IV were also significantly associated with shorter overall survival (median: 0.85 vs 9.4 months; p-value: 0.008).

Conclusion: Mutations in mitochondrial encoded ETC genes were more frequent in older patients and were significantly associated with mutations in TP53 and shorter overall survival. Elucidation of the mechanisms by which ETC mutations contribute to AML pathogenesis and progression will facilitate the development of novel therapeutic targets.