Chemotoxicity recovery of mitochondria in non‐Hodgkin lymphoma resulting in minimal residual disease

Abstract

Background The mechanisms responsible for resistant disease or recurrence of non-Hodgkin lymphoma (NHL) in children cover a wide spectrum from drug resistance to genetic mutations. A unique mechanism suggesting the role of mitochondria as the key energy source is studied following a clinical observation where pediatric Burkitt lymphoma (BL) specimens from patients on therapy were found to have increased copies of mitochondria DNA (mtDNA) in specimens which were shown to be positive for minimal residual disease and/or persistent disease (MRD/PD). This study hypothesized that the mitochondria play an important role in a cell’s recovery from toxicity via a compensatory increase in mtDNA. Procedure BL specimens with MRD/PD were assayed for mtDNA. An in vitro model was then designed using Ramos cell lines by exposing the lymphoma cells to varying concentrations of doxorubicin and vincristine for 1 hr; and allowing for recovery in culture over 7 days. DNA was extracted from aliquots over several days to determine mtDNA copy numbers by real-time polymerase chain reaction (PCR). Results Increased mtDNA copy numbers were found in clinical specimens with MRD/PD as well as in recovering Ramos cells from chemotoxicity. Conclusions The recovering lymphoma cells from the chemotoxic effects appeared to compensate by increasing mtDNA content, which may contribute to the clinical residual or resistant disease in some cases of childhood BL.

Possible Mitochondria-Associated Enzymatic Role in Non-Hodgkin Lymphoma Residual Disease

“…As the cells were allowed to recover, there is a marked increase in the expression of isocitrate dehydrogenase. One possible explanation for this observation could be the residual cells response to the toxic ROS effects of chemotoxicity which ultimately leads to a survival phenotype possibly via a compensatory mechanism [6]. …”

“…We further demonstrated that in a B-cell lymphoma culture model, surviving cells after chemotherapy exposure had higher mtDNA copy number [6]. The data suggested that increased copies of mtDNA per cell were found in tumor cells and residual or recovering cells.…”

Generation, function and diagnostic value of mitochondrial DNA copy number alterations in human cancers

“…Similar to head and neck cancers, Lin et al (2010) pointed out that mtDNA levels in ESCC were significantly related with tumor aggressiveness and increased in a stepwise manner from noncancerous lesions to cancerous ESCC nests and then to metastatic lymph nodes. In children with ALL and non-Hodgkin lymphoma, elevated mtDNA levels were recently reported to be associated with the positivity of minimal residual and/ or persistent disease and disease relapse (Egan et al, 2010;Kusao et al, 2008).…”

“…To date, characterization of mtDNA by utilizing the power of realtime PCR assays has revealed quantitative abnormalities of mtDNA content in an ample number of human cancers (Table 1), as either an increase in the vast proportion of acute lymphoblastic leukemia (ALL) (Egan et al, 2010), colorectal carcinoma (CRC) (Chen et al, 2011), endometrial cancer (Wang et al, 2005), esophageal squamous cell carcinoma (ESCC) (Lin et al, 2010), head and neck cancers , non-hodgkin lymphoma (Kusao et al, 2008), ovarian cancer (Wang et al, 2006), papillary thyroid carcinoma , prostate cancer and salivary gland oncocytoma (Heddi et al, 1996) or a decrease in most tumor tissues of advanced gastric cancer , breast cancer (Fan et al, 2009;Mambo et al, 2005;Tseng et al, 2006;Yu et al, 2007a), Ewing's sarcoma (EWS) (Yu et al, 2010), fibrolamellar carcinoma (Vivekanandan et al, 2010), hepatocellular carcinoma (HCC) Yamada et al, 2006;Yin et al, 2004;Vivekanandan et al, 2010), non-small cell lung cancer (NSCLC) (Lin et al, 2008a) and renal cell carcinoma (RCC) (Heddi et al, 1996;Meierhofer et al, 2004). The changes of mtDNA copy number in tumor specimens are usually retained within a fairly stable range (estimated to be less than two folds) in comparison with that in the nearby non-tumorous controls (Lee et al, 2005).…”

Effective use of small-interfering RNA to characterize residual B-cell non-Hodgkin lymphoma cells following chemotherapy

“…Mechanisms that contribute to MRD include the existence of mutations such as those found in the BCR-ABL protein kinase domain, variations in stem cell expression, and drug resistance resulting from exposure to chemotherapy treatment [4]. Another possible compensatory mechanism recently described implicated mitochondria as an energy source for a survival phenotype of residual malignant cells [5]. …”