Telomeres and telomerase in hematologic neoplasia

Ohyashiki, Junko H.; Sashida, Goro; Tauchi, Tetsuzo; Ohyashiki, Kazuma

doi:10.1038/sj.onc.1205075

Cited by 130 publications

(92 citation statements)

References 74 publications

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“…Nevertheless, the age-related loss of telomeric DNA in these cells suggests that telomerase activity in HSCs is insufficient to completely prevent telomere loss. Telomere length alterations have also been noted in myelodysplastic syndromes (MDS) and chronic myeloid leukaemia (CML), where telomere loss in HSCs may be associated with cellular senescence and ineffective haematopoiesis as well as contributing to genomic instability and subsequent leukaemic progression (Ohyashiki et al, 2002). These data support the idea that replicative potential of HSCs could be Figure 1 Telomere and telomerase dynamics in human stem cells.…”

Section: Telomeres and Telomerase In Haematopoietic Stem Cellsmentioning

confidence: 67%

“…Regardless of the derivation of CSCs, normal stem cells, committed progenitor cells, or differentiated cells (Clarke and Fuller, 2006), CSCs might have acquired immortality by mutational events in telomere-lengthening mechanisms, typically the activation of telomerase (Ohyashiki et al, 2002), considering that telomere shortening and cellular senescence are inevitable in these original cells (Figure 1), except for some MSCs. Theoretically, the inhibition of telomerase in CSCs to limit proliferation capacity and induce apoptosis, the stabilisation of telomeres in premalignant lesions to prevent the activation of telomerase and transformation to CSCs, and the identification of specific marker proteins in CSCs in each organ are likely to optimise screening and therapeutic interventions as novel anticancer strategies.…”

Section: Cancer Stem Cellsmentioning

confidence: 99%

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Telomere and telomerase in stem cells

2007

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Telomeres, guanine-rich tandem DNA repeats of the chromosomal end, provide chromosomal stability, and cellular replication causes their loss. In somatic cells, the activity of telomerase, a reverse transcriptase that can elongate telomeric repeats, is usually diminished after birth so that the telomere length is gradually shortened with cell divisions, and triggers cellular senescence. In embryonic stem cells, telomerase is activated and maintains telomere length and cellular immortality; however, the level of telomerase activity is low or absent in the majority of stem cells regardless of their proliferative capacity. Thus, even in stem cells, except for embryonal stem cells and cancer stem cells, telomere shortening occurs during replicative ageing, possibly at a slower rate than that in normal somatic cells. Recently, the importance of telomere maintenance in human stem cells has been highlighted by studies on dyskeratosis congenital, which is a genetic disorder in the human telomerase component. The regulation of telomere length and telomerase activity is a complex and dynamic process that is tightly linked to cell cycle regulation in human stem cells. Here we review the role of telomeres and telomerase in the function and capacity of the human stem cells.

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Section: Telomeres and Telomerase In Haematopoietic Stem Cellsmentioning

confidence: 67%

Section: Cancer Stem Cellsmentioning

confidence: 99%

Telomere and telomerase in stem cells

2007

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“…This finding is not totally unexpected, as alterations in telomere length and telomerase activity may facilitate cancer development by regulating genomic stability and cell lifespan 95 . In fact, a combination of shortened telomeres and increased telomerase activity is seen in most hematological and solid tumors 96 and mTERT transgenic mice with increased telomerase activity spontaneously develop cancer 97 . The best model to study telomere functions in stem cells has been the hematopoietic cell compartment 95,98 .…”

Section: Telomerase Activity and Telomere Length Regulate Cancer Stemmentioning

confidence: 99%

Somatic stem cells and the origin of cancer

2006

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647Most human cancers derive from a single cell targeted by genetic and epigenetic alterations that initiate malignant transformation. Progressively, these early cancer cells give rise to different generations of daughter cells that accumulate additional mutations, acting in concert to drive the full neoplastic phenotype 1,2 . As we have currently deciphered many of the gene pathways disrupted in cancer, our knowledge about the nature of the normal cells susceptible to transformation upon mutation has remained more elusive. Adult stem cells are those that show long-term replicative potential, together with the capacities of self-renewal and multi-lineage differentiation. These stem cell properties are tightly regulated in normal development, yet their alteration may be a critical issue for tumorigenesis. This concept has arisen from the striking degree of similarity noted between somatic stem cells and cancer cells, including the fundamental abilities to self-renew and differentiate. Given these shared attributes, it has been proposed that cancers are caused by transforming mutations occurring in tissue-specific stem cells 3-9 . This hypothesis has been functionally supported by the observation that among all cancer cells within a particular tumor, only a minute cell fraction has the exclusive potential to regenerate the entire tumor cell population 3,10-13 ; these cells with stem-like properties have been termed cancer stem cells. Cancer stem cells can originate from mutation in normal somatic stem cells that deregulate their physiological programs. Alternatively, mutations may target more committed progenitor cells or even mature cells, which become reprogrammed to acquire stem-like functions 14,15 In any case, mutated genes should promote expansion of stem/progenitor cells, thus increasing their predisposition to cancer development by expanding self-renewal and pluripotency over their normal tendency towards relative quiescency and proper differentiation.

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“…All of the ALL patients had precursor B-cell phenotype, and no patient with T-cell ALL was included in this study. Some of the clinical and molecular biological data concerning these patients were reported elsewhere (Ohyashiki et al, 2001(Ohyashiki et al, , 2002. All the samples of peripheral blood or bone marrow cells were separated using a Ficoll -Hypaque gradient, then cell pellets were immediately stored at À801C.…”

Section: Patients and Cellsmentioning

confidence: 99%

Quantitative relationship between functionally active telomerase and major telomerase components (hTERT and hTR) in acute leukaemia cells

Ohyashiki

Higuchi²,

Nagao³

et al. 2005

Br J Cancer

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Functionally active telomerase is affected at various steps including transcriptional and post-transcriptional levels of major telomerase components (hTR and human telomerase reverse transcriptase (hTERT)). We therefore developed a rapid and sensitive method to quantify hTERT and its splicing variants as well as the hTR by a Taqman real-time reverse transcriptase -polymerase chain reaction to determine whether their altered expression may contribute to telomere attrition in vivo or not. Fresh leukaemia cells obtained from 38 consecutive patients were used in this study. The enzymatic level of telomerase activity measured by TRAP assay was generally associated with the copy numbers of full-length hTERT þ a þ b mRNA (P ¼ 0.0024), but did not correlate with hTR expression (P ¼ 0.6753). In spite of high copy numbers of full-length hTERT mRNA, telomerase activity was low in some cases correlating with low copy numbers of hTR, raising the possibility that alteration of the hTR : hTERT ratio may affect functionally active telomerase activity in vivo. The spliced nonactive hTERT mRNA tends to be lower in patients with high telomerase activity, suggesting that this epiphenomenon may play some role in telomerase regulation. An understanding of the complexities of telomerase gene regulation in biologically heterogeneous leukaemia cells may offer new therapeutic approaches to the treatment of acute leukaemia.

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Telomeres and telomerase in hematologic neoplasia

Cited by 130 publications

References 74 publications

Telomere and telomerase in stem cells

Telomere and telomerase in stem cells

Somatic stem cells and the origin of cancer

Quantitative relationship between functionally active telomerase and major telomerase components (hTERT and hTR) in acute leukaemia cells

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