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• W2014807112 abstract "It is unlikely that the human genome was ever required to see us through to the degree of longevity to which we now aspire, so evolution appears to have left us with a blueprint for action through the first half of our lives and a vested interest in ageing research thereafter. One question central to the issue of senescence is how a cell can be aware of its own age, and it has seemed likely for a long time now that at least part of the answer lies in the lengths of the telomeres at the ends of each chromosome. Telomeres are repetitive sequences that decrease with every round of replication ( Blackburn, 1991), so telomere length could provide the basis for a ‘mitotic clock’ ticking once per division and providing a record of replication history. An essential element of the telomeric clock theory is that each cell is ‘born’ with an allocation of telomeric sequence. Once this allocation is used up and the telomeres reach a critical length (known as the Hayflick limit), the cell digs in its heels and exits the cell cycle ( Allsopp et al, 1992 ). This is all very well for those cells undergoing differentiation during development or tissue replenishment. Indeed, it could provide a failsafe mechanism to prevent over expansion and promote maturation. It would, however, be inappropriate for the germ cells and other stem cells that need both to self-renew and to maintain high proliferative potential. These cells are provided with an enzyme, telomerase, which can add extensions on to the telomeric repeats and compensate for the replicative loss ( Morrison et al, 1996 ). Net telomeric loss is then the result of a balance between replication rate and telomerase activity. Although the telomeric clock hypothesis has been around for some time, a number of recent papers have brought it once more to the fore. Firstly, it has been demonstrated that forcing the expression of telomerase in normal, human epithelial cells and fibroblasts allows them to divide apparently ad infinitum ( Bodnar et al, 1998 ). Furthermore, in mice lacking telomerase RNA the progressive decline in telomere length results, after four to six generations, in a decrease in clonogenic progenitors in the bone marrow, compromised spermatogenesis, small ovaries and decreased fertility, together with an increase in chromosome fusion and loss ( Lee et al, 1998 ). Together, these observations confirm the decisive role of telomere maintenance in determining life span, and provide strong support for the telomeric clock. Meanwhile, other work has suggested that ageing and telomere shortening may be of immediate relevance to clinical haematology, and it is this which we discuss below. The telomeres of peripheral blood cells decrease by around 40 bp per year throughout adult life ( Vaziri et al, 1994 ). As one might expect, variation between the telomere length in different blood cell types reflects their replication history: memory T cells, for instance, which have undergone extensive expansion, have telomeres significantly shorter than naive T cells ( Weng et al, 1995 ). The very fact that there is progressive shortening in peripheral blood cells carries strong implications, since it means either that the rate of telomere loss during haemopoietic replenishment accelerates with age, and/or that the haemopoietic stem cells themselves are losing telomeric sequence. In the latter case, those systems (including telomerase) which act to maintain telomere length in the stem cell compartment must fail to keep pace with the replicative loss due to self renewal. There is, in fact, increasing evidence that stem cell self-renewal may not be as fool-proof as one might have wished. Two studies published during the last year ( Champion et al, 1997 ; Gale et al, 1997 ) reveal clonal haemopoiesis (as indicated by a skewed X chromosome inactivation pattern, XCIP) to be surprisingly common among elderly women. The implications are that either the efficiency of stem cell self-renewal is biased by X allelic selection which could result over-extended periods in one of the two XCIPs becoming dominant, and/or that the stem cell pool becomes depleted during later life ( Champion et al, 1997 ). Telomeric senescence itself seems unlikely to be a potential cause of stem cell depletion, since mean telomere length in the peripheral blood, even in the ninth decade of life, remains well above the Hayflick limit ( Vaziri et al, 1994 ; Wynn et al, 1998 ). Nonetheless, the evidence of normal age-related clonality, together with the sharp increase in clonal disorders during later life ( Oscier, 1987), do suggest that the haemopoietic system may start to run down with time. Consistent with this, it has also been shown that telomere length drops during the cytokine supported ex-vivo culture of haemopoietic progenitors ( Engelhardt et al, 1998 ). A transient increase in telomerase activity over the first 2 weeks of culture appears to slow (but not halt) this process, Thereafter the telomerase activity returns to background levels and the telomeres shorten rapidly. In brief, the telomere maintenance mechanisms do not fully compensate for replicative loss in these early progenitors recruited to function under what are undoubtedly suboptimal and relatively demanding conditions. Indeed, if progressive telomere loss is part and parcel of normal haemopoiesis, then it seems likely that the problem would be aggravated by the imposition of extra demands on the stem cells. This was the reasoning behind two recent studies of the telomere loss in vivo following bone marrow transplantation ( Notaro et al, 1997 ; Wynn et al, 1998 ). By looking at donor–recipient pairs from allogeneic transplants it is possible to directly compare telomere lengths following reconstitution in the recipient with those following the same period of homeostasis in the donor. Since the cells are all donor-derived, variations between individuals are avoided and differences can be detected reliably from a relatively small sample size. The two studies took slightly different approaches: our own group concentrated on childhood recipients as the most likely to be affected by any clinical consequences in the long term, and measured average telomere lengths from all chromosomes; Notaro et al (1997 ) looked predominantly at adult recipients and made specific measurements of the telomere of the long arm of chromosome 7. The two studies yielded very similar results, indicating that reconstitution of haemopoiesis in transplant recipients is indeed associated with an extra decrease in telomere length of 0–1000 bp ( Wynn et al, 1998 ) or 79–1446 bp ( Notaro et al, 1997 ). A direct comparison with normal individuals studied at the same time shows that this is equivalent to approximately 15 years (range 0–40 years) ageing ( Wynn et al, 1998 ). These findings now raise a number of issues relevant to clinical haematology. Firstly, it is important to stress the limitations of the studies as they stand: as the study periods have been relatively short (between 4 and 83 months following transplantation), we do not yet know for sure whether telomere lengths continue to shorten at an accelerated rate, revert to the standard rate of 30–40 bp per year, or even stabilize and increase. In the data available so far there is no correlation between the extent of the additional loss and the time elapsed since transplant ( Notaro et al, 1997 ; our unpublished results), suggesting that once haemopoiesis is established the rate of telomere shortening probably stabilizes, at least in the short term. However, it is clear that much more detailed long-term studies will be required to resolve this issue with any real certainty. Secondly, and perhaps more importantly, we are still unsure of the probable clinical consequences of telomere shortening. If one is prepared to make the sweeping assumptions (a) that the increased frequency of clonal haemopoietic disorders in the elderly is chiefly a consequence of stem cell ageing, and (b) that the decrease in telomere length during reconstitution reflects a real and durable ageing effect equivalent to around 15 years, then one can predict a correspondingly earlier onset of clonal disorders in the long-term survivors of bone marrow transplantation ( Shay, 1998). However, these ‘ifs’ are still very large and (bone marrow transplantation being a relatively recent innovation) the absolute number of long-term survivors still relatively small, so it will probably be some time before the full consequences will become clear. What should we be doing with the information now at hand? The major aim, of course, must be to define the risk and, if it is found to be significant, to minimize it. As explained above, definition and quantification of the risks associated with the observed degree of haemopoietic ageing will require long-term studies, so it is important that we now begin to monitor the relevant patient groups and procedures in a manner that will facilitate meaningful follow-up studies. In particular, we should be looking out for other situations in which one might expect to encounter the problem. In aplastic anaemia patients, for example, stem cell numbers are depleted by an autoimmune response. Following immune-suppressive therapy, haemopoiesis recovers from what is probably a relatively small stem cell pool (analagous in this respect to the establishment of donor marrow following a transplant), and recovery is associated with an increased frequency of clonal disorders ( Fonsesca & Tefferi, 1997). This, then, is one condition under which increased replicative stress may play a role in the clinical outcome. In fact, a recent report of chromosomal abnormalities in patients with aplastic anaemia who showed markedly shortened telomere length appeared to support this contention ( Ball et al, 1998 ). We should also consider that, if a single round of ablation and recovery is damaging, then multiple rounds of chemotherapy are likely to be more so ( Testa et al, 1997 ; Engelhardt et al, 1998 ). In this respect, we should be paying particular attention to those AML or myeloma patients who receive autologous transplants after multiple rounds of chemotherapy and pre-transplant ablation. In all these cases it will be important to know whether early measurements of telomere shortening could be of any long-term prognostic value. In parallel, we should be using telomere length studies as an indicator of the degree of stress imposed during the manipulation of haemopoietic cells. There are a great many variables even between different bone marrow transplantation regimes, and one might expect the ageing effect to vary with stem cell source, method of collection and handling, patient conditioning and post-transplant treatment. One of the priorities will be to compare the properties of stem cells from bone marrow, peripheral blood and umbilical cord blood. Measurements of telomere length to date have usually relied on hybridization to restriction digested and electrophoretically separated DNA prepared from relatively large numbers of cells. In the studies of allogeneic transplant pairs described above, similar results were obtained using a telomere repeat probe (which averages information over all chromosomes; Wynn et al, 1998 ), and a subtelomeric probe specific for chromosome 7 ( Notaro et al, 1997 ). Although the chromosome-specific smears are more condensed and the resultant measurements more precise, it remains to be seen whether all chromosomes lose telomeric sequences at the same rate. In the future, the application of fluorescence in situ hybridization techniques promises to yield even more precise information from small numbers of cells ( Lansdorp et al, 1997 ), and should enable the detection of telomere length differences between rare populations of defined haemopoietic progenitors. In combination with PCR-mediated assays capable of measuring telomerase activity in very small number of cells, this approach should permit detailed analysis of the dynamics (rather than just the extent) of telomere loss. It should be stressed that Wynn et al (1998 ) and Notaro et al (1997 ) found reconstituted recipients in which no additional telomere shortening was detectable, and that Notaro et al (1997 ) noted a correlation between the number of infused cells and the degree of subsequent shortening. This suggests that there is a real prospect of reducing or avoiding the accelerated ageing phenomenon. However, it will not always be possible to alleviate matters simply by increasing the size of the graft, since the available numbers of repopulating cells are limiting. Indeed, there is currently much effort spent on refining conditions suitable for the expansion of stem cells precisely in order to boost the numbers available both for direct haemopoietic reconstitution and for manipulation in gene therapy ( Brugger & Kanz, 1996; Piacibello et al, 1997 ; Miller & Eaves, 1997). Furthermore, recent studies in the mouse suggest that the haemopoietic degeneration associated with serial transplantation is not a consequence of stem cell exhaustion, but that long-term reconstituting cells undergo considerable expansion which can be augmented by cytokine administration in vivo ( Iscove & Nawa, 1997). With what we now know about telomere shortening in vivo and in vitro, it would be appropriate to compare the effects of expansion protocols on telomere length. Indeed, the in vitro cultures in particular may provide an excellent opportunity for detailed study of the phenomena of accelerated haemopoietic ageing and how best to deal with it." @default.
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• W2014807112 title "Telomeres and haemopoiesis" @default.
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