Gattermann N, Berneburg M, Heinisch J, Aul C, Schneider W
Department of Hematology, Oncology, and Clinical Immunology, Heinrich-Heine-University, Düsseldorf, Germany.
Leukemia. 1995 Oct;9(10):1704-10.
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.
近年来，多种主要累及脑、心脏和肌肉的慢性退行性疾病已被证明是由线粒体DNA（mtDNA）突变引起的。4977碱基对的缺失（mtDNA-4977，也称为常见缺失）是线粒体肌病患者中最常见的异常情况。在正常衰老个体的各种组织中也发现了低比例的mtDNA-4977。这种缺失以及其他mtDNA缺失和点突变的积累被认为与正常细胞衰老有关。我们检查了63例接受心脏手术胸骨切开术且血液学正常的患者的血液和骨髓样本。使用有利于扩增携带大缺失分子的短周期PCR，我们在22例（35%）患者中检测到了常见缺失。在其中一名先证者中，鉴定出一种迄今未知的4867碱基对缺失（核苷酸8561 - 13429）。在每个样本中，mtDNA-4977的比例都非常低，因为检测总是需要对初级PCR产物进行引物移位再扩增。由于已知具有大缺失的mtDNA分子通过其比全长mtDNA更快复制的倾向而逐渐富集，所以检测到的少量mtDNA-4977可能集中在一小部分细胞中。在20例骨髓增生异常综合征（MDS）患者、20例急性髓系白血病（AML）患者和10例慢性髓系白血病（CML）患者中未检测到常见缺失。血液学正常个体中可检测到mtDNA-4977而克隆性髓系疾病中却不存在这一看似矛盾的现象，是由对携带常见缺失的自我更新干细胞的不同选择所解释的。在增殖应激情况下（例如在克隆性造血中持续增殖的干细胞中），选择似乎是有效的，而在正常稳态造血中，受影响的干细胞能够持续存在，因为它们很少进入细胞周期，因此能够耐受线粒体功能障碍。
