Description

Background

The establishment of donor-derived haemopoiesis in the recipients of allogeneic bone-marrow transplants (BMT) involves extensive proliferation of haemopoietic stem cells. The biological consequences of this replicative stress are ill defined, but any ageing effect would carry the risk of an increased frequency of clonal disorders during later life. We compared blood-cell mean telomere lengths in donor/recipient pairs.

Methods

Mean telomere length was calculated by in-gel hybridisation to leucocyte DNA from 56 normal individuals aged 0-96 years, and from 14 consecutive BMT recipients (aged 2-14 years) plus their respective donors (aged 2-46 years). Engraftment was confirmed by variable numbers of tandem repeats (VNTR) or gender analysis.

Findings

On average, blood-cell telomeres of transplant recipients were 0.4 kb (95% CI -0.2 to -0.6) shorter than those of their respective donors. This degree of telomere loss is equivalent to a median of 15 years (range 0-40) ageing in the healthy controls.

Interpretation

The kinetics of haemopoietic engraftment impose replicative stress on the haemopoietic stem cells, resulting in a pronounced ageing effect, which may be sufficient to accelerate the onset of clonal haemopoietic disorders usually associated with later life. Monitoring of haemopoietic status in BMT recipients as time since BMT increases will be important. Assessment of transplant protocols under development in terms of their effects on telomere shortening is also indicated.

Comment

The tail-end of chromosomes (telomeres) are important for chromosome stability and they progressively shorten with successive cell division of somatic cells. This is a cause of normal replicative senescence resulting in cell ageing. It may also possibly predispose to the onset of clonal disorders which are more common with advancing age. This study shows that in young individuals after BMT, there is significant telomere shortening amounting to a mean of 15 years compared to the donor bone marrow cells. Similar findings have already been reported previously and suggest that the replicative stress of bone marrow reconstitution accelerates the normal process of cell ageing. It remains to be shown whether this effect (which was highly variable) would correlate with the later onset of myelodysplasia or secondary leukaemia. However the authors express caution in relation to techniques of ex-vivo stem cell expansion which might itself increase telomere shortening still further.