Goldman Frederick D, Aubert Geraldine, Klingelhutz Al J, Hills Mark, Cooper Sarah R, Hamilton Wendy S, Schlueter Annette J, Lambie Karen, Eaves Connie J, Lansdorp Peter M
Department of Pediatrics, Division of Hematology/Oncology, University of Iowa Children's Hospital, Iowa City 52242, USA.
Blood. 2008 May 1;111(9):4523-31. doi: 10.1182/blood-2007-10-120204. Epub 2008 Feb 29.
Dyskeratosis congenita (DC) is an inherited bone marrow (BM) failure syndrome associated with mutations in telomerase genes and the acquisition of shortened telomeres in blood cells. To investigate the basis of the compromised hematopoiesis seen in DC, we analyzed cells from granulocyte colony-stimulating factor mobilized peripheral blood (mPB) collections from 5 members of a family with autosomal dominant DC with a hTERC mutation. Premobilization BM samples were hypocellular, and percentages of CD34(+) cells in marrow and mPB collections were significantly below values for age-matched controls in 4 DC subjects. Directly clonogenic cells, although present at normal frequencies within the CD34(+) subset, were therefore absolutely decreased. In contrast, even the frequency of long-term culture-initiating cells within the CD34(+) DC mPB cells was decreased, and the telomere lengths of these cells were also markedly reduced. Nevertheless, the different lineages of mature cells were produced in normal numbers in vitro. These results suggest that marrow failure in DC is caused by a reduction in the ability of hematopoietic stem cells to sustain their numbers due to telomere impairment rather than a qualitative defect in their commitment to specific lineages or in the ability of their lineage-restricted progeny to execute normal differentiation programs.
先天性角化不良（DC）是一种遗传性骨髓衰竭综合征，与端粒酶基因突变以及血细胞中端粒缩短有关。为了探究DC中造血功能受损的基础，我们分析了来自一个患有常染色体显性DC且携带hTERC突变的家族中5名成员的粒细胞集落刺激因子动员的外周血（mPB）样本中的细胞。动员前的骨髓样本细胞减少，4名DC受试者的骨髓和mPB样本中CD34(+)细胞的百分比显著低于年龄匹配的对照组。因此，直接克隆形成细胞虽然在CD34(+)亚群中以正常频率存在，但绝对数量减少。相比之下，CD34(+) DC mPB细胞中长期培养起始细胞的频率也降低，并且这些细胞的端粒长度也明显缩短。然而，体外成熟细胞的不同谱系数量正常。这些结果表明，DC中的骨髓衰竭是由于造血干细胞因端粒损伤而维持其数量的能力下降所致，而非其向特定谱系分化的定性缺陷，也不是其谱系受限后代执行正常分化程序的能力缺陷。
