Mitochondrial DNA mutations in primary leukemia cells after chemotherapy: clinical significance and therapeutic implications

Abstract

Mitochondrial DNA (mtDNA) codes for 13 respiratory chain subunits and is more vulnerable to damage than nuclear DNA due, in part, to a lack of histone protection and a weak repair capacity. While mtDNA alterations have been observed in human cancer, their roles in oncogenesis and chemosensitivity remain unclear. We investigated the relationship between mtDNA mutations, reactive oxygen species (ROS) generation, and clinical outcomes in chronic lymphocytic leukemia (CLL) patients. An analysis of mtDNA from 20 CLL patients revealed that primary CLL cells from patients with prior chemotherapy had a significantly higher frequency of heteroplasmic mutations than did those from untreated patients. Overall, mtDNA mutations appeared to be associated with increased ROS generation. Patients refractory to conventional therapeutic agents tended to have higher mutation rates than patients who responded to treatment. Analysis of paired blood samples from the same patient led to the identification of a heteroplasmic mutation in the cytochrome c oxidase II gene several months after chemotherapy. The mutation was associated with increased ROS generation. Our results suggest for the first time that chemotherapy with DNA-damaging agents may cause mtDNA mutations in primary leukemia cells, which often exist in heteroplasmy, and are associated with increased ROS generation.

New Haplotypes of the ATP Synthase Subunit 6 Gene of Mitochondrial DNA are Associated with Acute Lymphoblastic Leukemia in Saudi Arabia

“…Mitochondria also have fundamental functions in energy metabolism, production of reactive oxygen species (ROS), and apoptosis (Carew et al, 2003). Apoptosis performs a vital function in cancer growth and in the cellular response to anticancer agents.…”

“…The percentage of heteroplasmy in mitochondrial genome within each may differ by the time. This type of mutation, which changes the mitochondrial DNA, would lead polymorphism between individuals within same family regardless of carrying the same pathogenic mtDNA mutation (Wallace, 1992;Carew et al, 2003).…”

“…Mitochondria play vital functions in ATP metabolism, free radical generation, and regulation of apoptosis, subsequently changes in mitochondrial DNA would affect cellular energy capacities, increase oxidative stress, trigger ROS-mediated damage to DNA, and alter the cellular response to apoptosis induction by anticancer agents (Carew et al, 2003). Yacoub et al (2014) concluded that a thirteen mutant alleles in the d-loop region of mtDNA occurred with a high frequency and novel alleles and locations were also identified in that region as follows: 89 G insertions (40%), 95 G insertions (13%), 182 C/T substitutions (5%), 308 C insertions (19%), and 311 C insertions (80%).…”

“…Several studies demonstrated that mtDNA mutation is common in cancer (Lu et al, 2009;Cook and Higuchi, 2011). Mitochondria play vital functions in ATP metabolism, free radical generation, and regulation of apoptosis, subsequently changes in mitochondrial DNA would affect cellular energy capacities, increase oxidative stress, trigger ROS-mediated damage to DNA, and alter the cellular response to apoptosis induction by anticancer agents (Carew et al, 2003).…”

Platelet transfusion can mimic somatic mtDNA mutations

“…Accordingly, therapy-induced mutations were present at a low level. 4 Recently, Carew et al 5 reported a high mtDNA mutation rate in leukocytes of patients with chronic lymphatic leukemia (CLL) after chemotherapy. In this study, the mtDNA sequences of primary CLL cells were compared to the Cambridge reference sequence.…”