Assessing the role of mitochondrial DNA and Krebs cycle gene expression in pediatric-associated B-NHL minimal residual disease

The mechanisms responsible for resistant or recurrent disease in childhood non-Hodgkin lymphoma (NHL) are not yet fully understood. One potential pathway leading to resistant or recurrent disease suggests that mitochondria may be involved in altering the phenotype of surviving NHL tumor cells. The study, therefore, focused on silencing expression of citrate synthase and isocitrate dehydrogenase as a potential strategy to identify these genes as possible therapeutic targets for eradicating residual NHL cells.;Ramos cells, a Burkitt lymphoma cell line, were exposed to either doxorubicin (500 nM) or vincristine (12 nM) for one-hour duration with surviving cells being identified as residual. Cells were then transfected with siRNAs designed to silence the expression of both citrate synthase and isocitrate dehydrogenase, either individually or in combination. Lactate production and mtDNA copy numbers/cell were assessed over the 3-week culture period.;There was an observed direct relationship between mtDNA copy number and lactate production with citrate synthase siRNA transfected cells producing the least amount of lactate and lowest mtDNA copy number/cell while non-transfected cells produced the most lactate and highest mtDNA copy number/cell.;The direct relationship between mtDNA copy number and lactate production suggests that silencing the expression of citrate synthase in these residual cells may indicate a possible means in which resistant cells can be eradicated. While the results represent an in-vitro model, they provide a promising model that could ultimately lead to translating the findings clinically to potentially improve the prognosis for children diagnosed with Burkitt lymphoma.