Measurable immune dysfunction and telomere attrition in long-term allogeneic transplant recipients

Lewis, Nancy; Mullaney, MT; Mangan, Kenneth F.; Klumpp, Thomas R.; Rogatko, André; Broccoli, Dominique

doi:10.1038/sj.bmt.1704300

Cited by 19 publications

(17 citation statements)

References 51 publications

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“…In recipients of bone marrow transplants the hematopoietic system can suffer a dramatic telomere shortening, perhaps the equivalent to several decades of "aging" (Wynn et al, 1998). Some data suggest that long-term survivors of bone marrow transplants may suffer immune dysfunction as a consequence of the combination of the sudden loss of telomere length at the time of transplantation followed by normal age-related shortening (Lewis et al, 2004). This area of research, i.e.…”

Section: Do Telomere Biology and Telomerase Activity Determine Aging?mentioning

confidence: 99%

Telomerase and the aging process

Hornsby¹

2007

Experimental Gerontology

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The level of telomerase activity is important in determining telomere length in aging cells and tissues. Here evidence on the importance of telomerase activity is reviewed with respect to aging rates of mammalian species and the health and life span of individuals within a species. The significance of telomerase reactivation for both cancer development and for immortalizing cells for therapeutic processes is assessed. KeywordsTelomerase; telomeres; senescence; cancer; immortalization Telomeres are the specialized repetitive DNA sequences at the ends of the linear chromosomes, and associated proteins, that serve to maintain the integrity of the chromosomes. Telomerase is a ribonucleoprotein DNA polymerase complex that maintains telomere length. The complex comprises the protein telomerase reverse transcriptase (TERT, or hTERT in humans) and a catalytic RNA (TERC) (Shay and Wright, 2007). In the absence of telomerase activity telomeres progressively shorten. Telomerase activity is absent in most normal human somatic cells because of the lack of expression of TERT; TERC is usually present. On the other hand most mouse cells have telomerase activity (Blasco, 2005). Without telomerase, telomere shortening eventually limits the growth of cells, either by senescence, in cells with intact cell cycle checkpoints (a G1 cell cycle block), or by crisis in cells with inactivated checkpoints (telomeric end-to-end fusions cause chromosome breakage and mitotic catastrophe) (Shay and Wright, 2007). Expression of TERT in cells that otherwise lack telomerase activity causes cells to bypass senescence and crisis, and such cells are usually termed "immortalized." The significance of senescence, crisis and immortalization is explored further in this revew (see Figure 1). Do telomere biology and telomerase activity determine aging?The first aspect to this question is whether differences in aging rates among mammalian species are caused in whole or in part by species-specific differences in telomerase/telomere biology. A very brief consideration of this question will show that this is unlikely. Mice are short-lived compared to humans, yet mice have long telomeres and adult mouse somatic cells often have telomerase activity (Blasco, 2005). On the other hand, humans have relatively short telomeres, even when compared to closely related primates (Kakuo et al., 1999), and telomerase activity

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Section: Do Telomere Biology and Telomerase Activity Determine Aging?mentioning

confidence: 99%

Telomerase and the aging process

Hornsby¹

2007

Experimental Gerontology

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“…It is unlikely that telomere shortening after HCT is sufficient by itself to cause hematologic dysfunction, although it may be additive or synergistic to other changes in the bone marrow environment. 26 There has been no consistent correlation between age of the donor or recipient, nor the type and extent of pre-HCT therapy, with after-HCT changes in telomere length. 27 Interestingly, mononuclear cells of HC transplant UCB recipients have significantly longer telomeres compared with allogeneic PB HC transplant recipients, and it has been hypothesized that UCB transplants may provide patients with replicative "reserve" potential and a delay in the onset of hematologic disorders.…”

Section: Introductionmentioning

confidence: 99%

Donor cell leukemia: insight into cancer stem cells and the stem cell niche

Flynn

Kaufman

2006

Blood

127

108

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“…Patients developing graftvs.-host disease following allogeneic transplantation may have even more severe defects in both cellular and humoral immunity that prolong immune reconstitution. Telomere attrition has recently been added as a contributing factor to immune dysfunction in long-term allogeneic transplant recipients (85).…”

Section: Monitoring Bone Marrow Reconstitutionmentioning

confidence: 99%

Hematologic aspects of myeloablative therapy and bone marrow transplantation

Riley

Idowu

Chesney

et al. 2005

Clinical Laboratory Analysis

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The transplantation of bone marrow cells or isolated hematopoietic stem cells from the bone marrow or peripheral blood is a widely utilized form of therapy for patients with incurable diseases of the hematopoietic and immune systems. Successful engraftment of the transplanted stem cells in an adequately prepared recipient normally leads to bone marrow reconstitution over a period of several weeks, accompanied by more gradual reconstitution of the immune system. Since the recipient is profoundly ill during the initial treatment period, laboratory data is critical for monitoring engraftment, detecting residual/recurrent disease, and identifying problems that may delay bone marrow reconstitution or lead to other medical complications. Accurate blood cell counts are imperative, and most bone marrow transplantation patients undergo periodic monitoring with bone marrow aspirates and biopsies with cytogenetic, molecular, and multiparametric flow cytometric studies. The potential complications of bone marrow transplantation include engraftment failure and delayed engraftment, infection, residual bone marrow disease, acute and chronic graft versus host disease, myelofibrosis, therapy-related acute leukemia, post-transplant lympho-proliferative disorders, and toxic myelopathy.

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Measurable immune dysfunction and telomere attrition in long-term allogeneic transplant recipients

Cited by 19 publications

References 51 publications

Telomerase and the aging process

Telomerase and the aging process

Donor cell leukemia: insight into cancer stem cells and the stem cell niche

Hematologic aspects of myeloablative therapy and bone marrow transplantation

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