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Blood, 1 September 2004, Vol. 104, No. 5, pp. 1273-1280. Prepublished online as a Blood First Edition Paper on May 4, 2004; DOI 10.1182/blood-2003-08-2935. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-08-2935v1 104/5/1273    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kuramoto, K. Articles by Dunbar, C. E. Search for Related Content PubMed PubMed Citation Articles by Kuramoto, K. Articles by Dunbar, C. E. Related Collections Hematopoiesis and Stem Cells Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY The impact of low-dose busulfan on clonal dynamics in nonhuman primates Ken Kuramoto, Dean Follman, Peiman Hematti, Stephanie Sellers, Mikko O. Laukkanen, Ruth Seggewiss, Mark E. Metzger, Allen Krouse, Robert E. Donahue, Christof von Kalle, and Cynthia E. Dunbar From the Hematology Branch, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, Bethesda, MD; the Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD; and the Division of Experimental Hematology, Children's Research Foundation, Cincinnati Children's Hospital Medical Center, Cincinnati, OH. An understanding of the number and contribution of individual pluripotent hematopoietic stem cells (HSCs) to the formation of blood lineages has important clinical implications for gene therapy and stem cell transplantation. We have been able to efficiently mark rhesus macaque long-term repopulating stem and progenitor cells with retroviral vectors, and track their in vivo contributions to hematopoiesis using the linear amplification mediated–polymerase chain reaction (LAM-PCR) technique of insertion site analysis. We assessed the impact of busulfan on contributions of individual retrovirally marked clones to hematopoiesis. There were 2 macaques that received transplants of retrovirally transduced CD34+ cells 2 years previously that were then treated with 4 mg/kg busulfan. Despite only transient and mild suppression of peripheral blood counts, the numbers of individual stem/progenitor clones contributing to granulocyte production decreased dramatically, by 80% in the first monkey and by 60% in the second monkey. A similar impact was seen on clones contributing to T cells. The clone numbers recovered gradually back toward baseline by 5 months following busulfan in the first monkey and by 3 months in the second monkey, and have remained stable for more than one year in both animals. Tracking of individual clones with insertion-site–specific primers suggested that clones contributing to hematopoiesis prior to busulfan accounted for the majority of this recovery, but that some previously undetected clones began to contribute during this recovery phase. These results indicate that even low-dose busulfan significantly affects stem and progenitor cell dynamics. The clonal diversity of hematopoiesis was significantly decreased after even a single, clinically well-tolerated dose of busulfan, with slow but almost complete recovery over the next several months, suggesting that true long-term repopulating stem cells were not permanently deleted. However, the prolonged period of suppression of many clones suggests that transplanted HSCs may have a marked competitive advantage if they can engraft and proliferate during this time period, and supports the use of this agent in nonmyeloablative regimens CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. R. Bauer Jr, M. Hai, L. M. Tuschong, T. H. Burkholder, Y.-c. Gu, R. A. Sokolic, C. Ferguson, C. E. Dunbar, and D. D. Hickstein Correction of the disease phenotype in canine leukocyte adhesion deficiency using ex vivo hematopoietic stem cell gene therapy Blood, November 15, 2006; 108(10): 3313 - 3320. [Abstract] [Full Text] [PDF] M. O. Laukkanen, K. Kuramoto, B. Calmels, M. Takatoku, C. von Kalle, R. E. Donahue, and C. E. Dunbar Low-dose total body irradiation causes clonal fluctuation of primate hematopoietic stem and progenitor cells Blood, February 1, 2005; 105(3): 1010 - 1015. [Abstract] [Full Text] [PDF]

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