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


METHODS
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.
Kusao
Ian
I
Department of Physiology, University of Hawaii, Honolulu, Hawaii 96816, USA.
Agsalda
Melissa
M
Troelstrup
David
D
Villanueva
Nicolas
N
Shiramizu
Bruce
B
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000009:adverse effects*; D045744:Cell Line, Tumor; D004272:DNA, Mitochondrial / Q000032:analysis; D018628:Gene Dosage; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018365:Neoplasm, Residual
D000970:Antineoplastic Agents; D004272:DNA, Mitochondrial; D000255:Adenosine Triphosphate