Mitochondrial DNA heteroplasmy in radiation induced myelodysplasia and leukaemia

Abstract

Haematological defects observed in clonal deletions of mtDNA and the inhibition of mitochondrial function by benzene and chloramphenicol, suggest a role for mtDNA in the pathogenesis of radiation - induced preleukaemia (MDS). The fact that leukaemia cells contain abnormal mitochondria and abnormally structured mtDNA, makes it reasonable to assume mtDNA mutations could be central to the pathogenesis of both MDS and leukaemia. It was decided to examine MDS patients for the presence of mtDNA length mutations (dimers and cocantameres). Such topological forms have already been reported in the literature in association with human leukaemia. These steric considerations suggest that mtDNA dimers are probably non-functional due to supercoiling. Thus, it was felt that a progressive accumulation of non-functional dimers in the haematopoietic compartment could account for many of the clinical features associated with MDS. Transmission electron microscopy was used to examine haematopoietic mtDNA in the bone marrow of six patients with MDS. Abnormal mtDNA dimer formation was found in all instances. The proportional number of these dimers were found to roughly correlate with the Myeloid/ Erythroid cell ratio in the bone marrow, and it appeared likely that the dimers were generated in the myeloid compartment during early MDS.