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Blood, 15 October 2008, Vol. 112, No. 8, pp. 3186-3193.
Prepublished online as a Blood First Edition Paper on July 18, 2008; DOI 10.1182/blood-2008-03-143925.
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Submitted March 6, 2008
Accepted July 4, 2008
Hematopoiesis is not clonal in healthy elderly women
Sabina I Swierczek, Neeraj Agarwal, Roberto H Nussenzveig, Gerald Rothstein, Andrew Wilson, Andrew Artz, and Josef T Prchal*
Division of Hematology, University of Utah School of Medicine, Salt Lake City, Utah, United States
Special Genetics, ARUP Laboratories, Salt Lake City, Utah, United States
Division of Geriatrics, University of Utah School of Medicine, Salt Lake City, Utah, United States
Section of Hematology-Oncology, University of Chicago, Chicago, Illinois, United States
Veterans Affairs Medical Center, Salt Lake City, Utah, United States
* Corresponding author; email: josef.prchal{at}hsc.utah.edu.
Clonality assays, based on X-chromosome inactivation, discriminate active from inactive alleles. Skewing of X-chromosome allelic-usage, based on preferential methylation of one of the HUMARA alleles, was reported as evidence of clonal hematopoiesis in ~30% elderly women. Using a quantitative, transcriptionally-based clonality assay, we reported X-chromosome transcribed allelic-ratio in blood cells of healthy women consistent with random X-inactivation of 8 embryonic hematopoietic stem-cells. Furthermore, we did not detect clonal hematopoiesis in >200 healthy non-elderly women. In view of the susceptibility of aging hematopoietic stem cells to epigenetic dysregulation, we re-investigated the issue of clonality in elderly women. Forty healthy women (age 65-92, mean 81.3 years), were tested by a novel, quantitative qPCR transcriptional clonality assay. We did not detect clonal hematopoiesis in any of the tested subjects. We also tested DNA from the same granulocyte samples using the methylation-based HUMARA assay, and confirmed previous reports of ~30% extensively skewed or monoallelic methylation; in agreement with likely age related deregulated methylation of the HUMARA gene locus. We conclude that the transcriptionally-based X-chromosome clonality assays are suitable for evaluation of clonal hematopoiesis in elderly women.
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