Detection of the ageing-associated 5-Kb common deletion of mitochondrial DNA in blood and bone marrow of hematologically normal adults. Absence of the deletion in clonal bone marrow disorders.

In recent years, a variety of chronic degenerative diseases that mainly involve brain, heart and muscle have been shown to result from mutations in mitochondrial DNA (mtDNA). A 4977-bp deletion (mtDNA-4977, also known as the common deletion) is the most frequent abnormality in patients with mitochondrial myopathies. A low percentage of mtDNA-4977 is also found in various tissues of normal ageing individuals. Accumulation of this deletion as well as other mtDNA deletions and point mutations is thought to contribute to normal cell ageing. We examined blood and bone marrow samples of 63 hematologically normal patients undergoing sternotomy for cardiac surgery. Using short-cycle PCR, which favors the amplification of molecules carrying large deletions, we detected the common deletion in 22 (35%) of the patients. In one of the probands, a hitherto unknown 4867-bp deletion was identified (nt 8561-13429). In each sample the percentage of mtDNA-4977 was very low, since detection always required primer-shift reamplification of a primary PCR product. Because mtDNA molecules with large deletions are known to be progressively enriched through their tendency to replicate more rapidly than full-size mtDNA, the small amount of mtDNA-4977 detected is likely to be concentrated in a small fraction of cells. The common deletion was not detectable in 20 patients with myelodysplastic syndromes (MDS), 20 patients with acute myeloid leukemia (AML), and 10 patients with chronic myeloid leukemia (CML). The seeming paradox of detectability of mtDNA-4977 in hematologically normal individuals and its absence in clonal myeloid disorders is explained by varying selection against self-renewing stem cells harboring the common deletion. Selection appears to be effective under circumstances of proliferative stress (eg among continuously proliferating stem cells in clonal hematopoiesis), whereas in normal steady-state hematopoiesis, affected stem cells persist because they are rarely recruited into cell cycle and can thus tolerate mitochondrial dysfunction.