Telomere shortening in leucocyte subsets of long‐term survivors of allogeneic bone marrow transplantation

Abstract

Summary. Recent studies have demonstrated excessive telomeric shortening in peripheral blood leucocytes of bone marrow transplant (BMT) recipients. This finding has raised concerns about accelerated haemopoietic ageing that might predispose to clonal disorders and late graft failure. We studied the peripheral blood neutrophils and T cells of 14 fully engrafted long-term survivors of BMT.We found that in both neutrophils and T cells there was significant telomere shortening in the recipient (0·6 and 0·5 kb, respectively; P < 0·001 and < 0·04, respectively). We found no relationship between degree of shortening and the nucleated cell dose given at the time of transplant. We also demonstrated significantly longer telomeres in T cells than neutrophils from the same individual (mean 11·6 kb and 10·6 kb, respectively; P¼0·0001).We propose mechanisms to account for these observations. The replicative stress that causes this telomere shortening does not necessarily occur at the level of the most primitive haemopoietic stem cell.

Telomere length in breast cancer patients before and after chemotherapy with or without stem cell transplantation

“…Previously, it was assumed that if small numbers of CD34+ cells are reinfused, these cells may have to undergo more cell divisions than larger numbers, for a similar net haematopoietic effect (Notaro et al, 1997). However, no relationship was found between the degree of TRF length shortening and the number of reinfused CD34+ cells in recent studies Wynn et al, 1999) and our data support this. Possibly, in vitro culturing of CD34+ cells may provide more insight into the balance between cell proliferation and the ability to upregulate telomerase activity in individuals, leading to (change of) telomere length in vivo.…”

“…However, in this study no difference in the leukocyte differentiations was found in either group before or after treatment, and TRF length in our leukocyte samples is therefore unlikely to be affected by such a difference. Furthermore, variable differences of TRF length of neutrophils and T lymphocytes have been reported, ranging from approximately 1 kb (Wynn et al, 1999) to none (Martens et al, 2000). In light of these data, we consider leukocytes, in line with Wynn et al (1998), sufficient for the purpose of this study.…”

“…In analogy to the pioneering study by Wynn et al (1998), we chose unselected leukocytes to measure TRF length and telomerase activity in. In recent studies, it has been suggested that lymphocytes may have a larger TRF length than neutrophils (Wynn et al, 1999;Robertson et al, 2000). Although TRF length of T lymphocytes and neutrophils was shown to be equally affected by stem cell transplantation (Wynn et al, 1999), in case of a change in the relative proportions of these cells, it might be slightly more difficult to draw conclusions from overall leukocyte TRF length.…”

“…In recent studies, it has been suggested that lymphocytes may have a larger TRF length than neutrophils (Wynn et al, 1999;Robertson et al, 2000). Although TRF length of T lymphocytes and neutrophils was shown to be equally affected by stem cell transplantation (Wynn et al, 1999), in case of a change in the relative proportions of these cells, it might be slightly more difficult to draw conclusions from overall leukocyte TRF length. However, in this study no difference in the leukocyte differentiations was found in either group before or after treatment, and TRF length in our leukocyte samples is therefore unlikely to be affected by such a difference.…”

“…However, mean TRF length of nucleated blood cells has been shown to be widely variable between these controls (Notaro et al, 1997;Akiyama et al, 1998;Ball et al, 1998;Wynn et al, 1998;Lee et al, 1999). Additionally, samples were drawn at a wide range of time after PBSCT, ranging from 1.6 months to over 10 years (Akiyama et al, 1998;Wynn et al, 1999). Finally, as TRF dynamics were shown to be different in the various stages of life (Zeichner et al, 1999), predictive value for the adult setting may not automatically be assumed from these paediatric data.…”