DETECTION OF THE AGING-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 mainl y involve brain, heart and muscle have been shown to result from mutat ions in mitochondrial DNA (mtDNA). A 4977-bp deletion (mtDNA(-4977), a lso known as the common deletion) is the most frequent abnormality in patients with mitochondrial myopathies. A low percentage of mtDNA(-497 7) is also found in various tissues of normal ageing individuals. Accu mulation of this deletion as well as other mtDNA deletions and point m utations is thought to contribute to normal cell ageing. We examined b lood and bone marrow samples of 63 hematologically normal patients und ergoing sternotomy for cardiac surgery. Using short-cycle PCR, which f avors the amplification of molecules carrying large deletions, we dete cted the common deletion in 22 (35%) of the patients. In one of the pr obands, a hitherto unknown 4867-bp deletion was identified (nt 8561-13 429). In each sample the percentage of mtDNA(-4977) was very low, sinc e 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 ra pidly 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 syndro mes (MDS), 20 patients with acute myeloid leukemia (AML), and 10 patie nts with chronic myeloid leukemia (CML). The seeming paradox of detect ability 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. Select ion appears to be effective under circumstances of proliferative stres s (eg among continuously proliferating stem cells in clonal hematopoie sis), whereas in normal steady-state hematopoiesis, affected stem cell s persist because they are rarely recruited into cell cycle and can th us tolerate mitochondrial dysfunction.