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Blood, 1 April 2002, Vol. 99, No. 7, pp. 2387-2396
HEMATOPOIESIS
Early hematopoietic reconstitution after clinical stem cell
transplantation: evidence for stochastic stem cell behavior and limited
acceleration in telomere loss
Ian Thornley,
Robert Sutherland,
Robert Wynn,
Rakash Nayar,
Lillian Sung,
George Corpus,
Thomas Kiss,
Jeff Lipton,
John Doyle,
Fred Saunders,
Suzanne Kamel-Reid,
Melvin Freedman, and
Hans Messner
From the Division of Hematology/Oncology, the Hospital
for Sick Children and Department of Medical Oncology and Hematology,
University Health Network, University of Toronto, Ontario, Canada, and
Department of Haematology, Royal Manchester Children's Hospital,
United Kingdom.
Our inability to purify hematopoietic stem cells (HSCs) precludes
direct study of many aspects of their behavior in the clinical hematopoietic stem cell transplantation (HSCT) setting. We indirectly assessed stem/progenitor cell behavior in the first year after HSCT by
examining changes in neutrophil telomere length, X-inactivation ratios,
and cycling of marrow progenitors in 25 fully engrafted allogeneic HSCT
recipients. Donors were sampled once and recipients at engraftment and
2 to 6 months and 12 months after HSCT. Telomere length was measured by
an in-gel hybridization technique, X-inactivation ratios were measured
by the human androgen receptor assay, and cell cycle status was
determined by flow cytometric analysis of pyronin Y- and Hoechst
33342-stained CD34+CD90+ and
CD34+CD90 marrow cells. Compared with their
donors, recipients' telomeres were shortened at
engraftment ( 424 base pairs [bp]; P < .0001), 6 months (495 bp; P = .0001) after HSCT, and 12 months
after HSCT (565 bp; P < .0001). There was no
consistent pattern of change in telomere length from 1 to 12 months
after HSCT; marked, seemingly random, fluctuations were common. In 11 of 11 informative recipients, donor X-inactivation ratios were
faithfully reproduced and maintained. The proportion of
CD34+CD90+ progenitors in S/G2/M
was 4.3% in donors, 15.7% at 2 to 6 months (P < .0001)
after HSCT, and 11.5% at 12 months after HSCT
(P < .0001, versus donors; P = .04, versus
2-6 months). Cycling of CD34+ CD90
progenitors was largely unchanged. We infer that (1) HSCT-induced accelerated telomere loss is temporary and unlikely to promote graft
failure or clonal hematopoietic disorders and (2) the striking fluctuations in telomere length and variation in pattern of telomere loss reflect stochastic determination of HSC fate after HSCT.
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