Submitted October 26, 2007
Accepted February 24, 2008
Characterization of primitive hematopoietic cells from patients with dyskeratosis congenita
Frederick D Goldman*, Geraldine Aubert, Al J Klingelhutz, Mark Hills, Sarah R Cooper, Wendy S Hamilton, Annette J Schlueter, Karen Lambie, Connie J Eaves, and Peter M Lansdorp
Division of Hematology/Oncology, Department of Pediatrics, University of Iowa Children's Hospital, Iowa City, Iowa, United States
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
Department of Microbiology, University of Iowa, Iowa City, Iowa, United States
Department of Pathology, University of Iowa, Iowa City, Iowa, United States
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
Department of Medicine, Division of Hematology, University of British Columbia, Vancouver, British Columbia, Canada
* Corresponding author; email: frederick-goldman{at}uiowa.edu.
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 five members of a family with autosomal dominant DC with a hTERC mutation. Pre-mobilization BM samples were hypocellular and percentages of CD34+ cells in marrow and mPB collections were significantly below values for age-matched controls in four 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.
