Telomeres in the Haemopoietic System

Lansdorp, Peter M.; Poon, Steven S.S.; Chavez, Elizabeth A.; Dragowska, Visia; Zijlmans, Mark; Bryan, Tracy M.; Reddel, Roger R.; Egholm, Michael; Bacchetti, Silvia; Martens, Uwe M.

doi:10.1002/9780470515433.ch14

Cited by 16 publications

(6 citation statements)

References 31 publications

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“…46,47 In normal HSCs, telomerase seems unable to prevent telomere shortening with replication, probably because of the low level of expression. [48][49][50] Telomerase expression is upregulated with cell cycle activation, and as a consequence, expression levels are higher in more committed CD34 þ 38 þ progenitors compared to the CD34 þ 38À population.…”

Section: Telomeres and Stem Cell Turnover In Normal Hematopoiesismentioning

confidence: 99%

Telomere length dynamics in normal hematopoiesis and in disease states characterized by increased stem cell turnover

Brümmendorf

Balabanov

2006

Leukemia

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Telomeres both reflect and limit the replicative lifespan of normal somatic cells. Immature sub-populations of human CD34 þ 38À hematopoietic stem cell (HSC) can be identified in vitro based on their growth kinetics and telomere length. Fluorescence in situ hybridization and flow cytometry (flow-FISH) has been used to characterize telomere length dynamics as a surrogate marker for HSC turnover in vivo. Investigations in normal steady-state hematopoiesis provided the basis for follow-up studies in model scenarios characterized by increased HSC turnover. Disorders with underlying malignant transformation of HSC (e.g., chronic myeloid leukemia (CML)) can be discriminated from disease states with increased HSC turnover rates secondary to depletion of the stem cell compartment, for example, as in defined bone marrow failure syndromes. In some of these model scenarios, the degree of telomere shortening can be correlated with disease duration, disease stage and severity as well as with response to diseasemodifying treatment strategies. Whether increased telomere shortening represents a causal link between HSC turnover, replicative senescence and/or the induction of genetic instability in acquired HSC disorders remains to be shown. However, data from congenital disorders, like dyskeratosis congenita (DKC), suggest that disturbed telomere maintenance may play a role for replicative exhaustion of the HSC pool in vivo.

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Section: Telomeres and Stem Cell Turnover In Normal Hematopoiesismentioning

confidence: 99%

Telomere length dynamics in normal hematopoiesis and in disease states characterized by increased stem cell turnover

Brümmendorf

Balabanov

2006

Leukemia

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“…However, a significant minority of cancers use alternative lengthening of telomeres (ALT), to maintain telomeres (55). The telomeres in typical cells displaying ALT are highly heterogeneous in length, and while many are much longer than normal human telomeres, others are abnormally short (6,38,56,65). The telomeres of ALT cancers can copy DNA from telomere to telomere and therefore are thought to maintain their lengths by recombination (17).…”

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confidence: 99%

Mutant Telomeric Repeats in Yeast Can Disrupt the Negative Regulation of Recombination-Mediated Telomere Maintenance and Create an Alternative Lengthening of Telomeres-Like Phenotype

Bechard

Bütüner

Peterson

et al. 2009

Molecular and Cellular Biology

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Some human cancers maintain telomeres using alternative lengthening of telomeres (ALT), a process thought to be due to recombination. In Kluyveromyces lactis mutants lacking telomerase, recombinational telomere elongation (RTE) is induced at short telomeres but is suppressed once telomeres are moderately elongated by RTE. Recent work has shown that certain telomere capping defects can trigger a different type of RTE that results in much more extensive telomere elongation that is reminiscent of human ALT cells. In this study, we generated telomeres composed of either of two types of mutant telomeric repeats, Acc and SnaB, that each alter the binding site for the telomeric protein Rap1. We show here that arrays of both types of mutant repeats present basally on a telomere were defective in negatively regulating telomere length in the presence of telomerase. Similarly, when each type of mutant repeat was spread to all chromosome ends in cells lacking telomerase, they led to the formation of telomeres produced by RTE that were much longer than those seen in cells with only wild-type telomeric repeats. The Acc repeats produced the more severe defect in both types of telomere maintenance, consistent with their more severe Rap1 binding defect. Curiously, although telomerase deletion mutants with telomeres composed of Acc repeats invariably showed extreme telomere elongation, they often also initially showed persistent very short telomeres with few or no Acc repeats. We suggest that these result from futile cycles of recombinational elongation and truncation of the Acc repeats from the telomeres. The presence of extensive 3 overhangs at mutant telomeres suggests that Rap1 may normally be involved in controlling 5 end degradation.

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“…These progenitor cells represent only about 0.01% of all bone marrow cells (Lansdorp et al 1997). A fine balance between self-renewal and differentiation is required by the HSCs in order to maintain the complex hematopoietic system throughout life.…”

Section: Introductionmentioning

confidence: 99%

Telomeres, senescence, and hematopoietic stem cells

Zimmermann

Martens

2007

Cell Tissue Res

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The replicative lifespan of normal somatic cells is restricted by the erosion of telomeres, which are protective caps at the ends of linear chromosomes. The loss of telomeres induces antiproliferative signals that eventually lead to cellular senescence. The enzyme complex telomerase can maintain telomeres, but its expression is confined to highly proliferative cells such as stem cells and tumor cells. The immense regenerative capacity of the hematopoietic system is provided by a distinct type of adult stem cell: hematopoietic stem cells (HSCs). Although blood cells have to be produced continuously throughout life, the HSC pool seems not to be spared by aging processes. Indeed, limited expression of telomerase is not sufficient to prevent telomere shortening in these cells, which is thought ultimately to limit their proliferative capacity. In this review, we discuss the relevance of telomere maintenance for the hematopoietic stem cell compartment and consider potential functions of telomerase in this context. We also present possible clinical applications of telomere manipulation in HSCs and new insights affecting the aging of the hematopoietic stem cell pool and replicative exhaustion.

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Telomeres in the Haemopoietic System

Cited by 16 publications

References 31 publications

Telomere length dynamics in normal hematopoiesis and in disease states characterized by increased stem cell turnover

Telomere length dynamics in normal hematopoiesis and in disease states characterized by increased stem cell turnover

Mutant Telomeric Repeats in Yeast Can Disrupt the Negative Regulation of Recombination-Mediated Telomere Maintenance and Create an Alternative Lengthening of Telomeres-Like Phenotype

Telomeres, senescence, and hematopoietic stem cells

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