A 'telomere-associated secretory phenotype' cooperates with BCR-ABL to drive malignant proliferation of leukemic cells.

Telomere biology is frequently associated with disease evolution in human cancer and dysfunctional telomeres have been demonstrated to contribute to genetic instability. In BCR-ABL(+) chronic myeloid leukemia (CML), accelerated telomere shortening has been shown to correlate with leukemia progression, risk score and response to treatment. Here, we demonstrate that proliferation of murine CML-like bone marrow cells strongly depends on telomere maintenance.

CEBP factors regulate telomerase reverse transcriptase promoter activity in whey acidic protein-T mice during mammary carcinogenesis.

Telomerase is activated in the majority of invasive breast cancers, but the time point of telomerase activation during mammary carcinogenesis is not clear. We have recently presented a transgenic mouse model to study human telomerase reverse transcriptase (TERT) gene expression in vivo (hTERTp-lacZ). In the present study, hTERTp-lacZxWAP-T bitransgenic mice were generated to analyze the mechanisms responsible for human and mouse TERT upregulation during tumor progression in vivo.

Telomere dysfunction puts the brakes on oncogene-induced cancers.

EMBO J 31 13, 2839–2851 (2012); published online May 08 2012 Senescence represents a major tumour suppressor checkpoint activated by telomere dysfunction or cellular stress factors such as oncogene activation. In this issue of , Suram et al (2012) reveal a surprising interconnection between oncogene activation and telomere dysfunction induced senescence. The study supports an alternative model of tumour suppression, indicating that oncogene-induced accumulation of telomeric DNA damage contributes to the induction of senescence in telomerase-negative tumours.

Disruption of Trp53 in livers of mice induces formation of carcinomas with bilineal differentiation.

Background & Aims: p53 limits the self-renewal of stem cells from various tissues. Loss of p53, in combination with other oncogenic events, results in aberrant self-renewal and transformation of progenitor cells. It is not known whether loss of p53 is sufficient to induce tumor formation in liver.

Telomere dysfunctional environment induces loss of quiescence and inherent impairments of hematopoietic stem cell function.

Previous studies have shown that telomere dysfunction induces alteration in the systemic (circulatory) environment impairing the differentiation of hematopoietic stem cells (HSCs) but these defects can be reverted by re-exposing HSCs to an environment with functional telomeres. In contrast, HSC intrinsic telomere dysfunction induces permanent and irreversible limitations in the repopulation capacity partially depending on the induction of checkpoints such as cell cycle arrest, differentiation, or apoptosis. It is currently unknown whether telomere dysfunctional environment can induce irreversible, cell intrinsic defects impairing the function of HSCs.

Regeneration of the exocrine pancreas is delayed in telomere-dysfunctional mice.

Introduction: Telomere shortening is a cell-intrinsic mechanism that limits cell proliferation by induction of DNA damage responses resulting either in apoptosis or cellular senescence. Shortening of telomeres has been shown to occur during human aging and in chronic diseases that accelerate cell turnover, such as chronic hepatitis. Telomere shortening can limit organ homeostasis and regeneration in response to injury.

Sod2 haploinsufficiency does not accelerate aging of telomere dysfunctional mice.

Telomere shortening represents a causal factor of cellular senescence. At the same time, several lines of evidence indicate a pivotal role of oxidative DNA damage for the aging process in vivo. A causal connection between the two observations was suggested by experiments showing accelerated telomere shorting under conditions of oxidative stress in cultured cells, but has never been studied in vivo.

Alterations of the systemic environment are the primary cause of impaired B and T lymphopoiesis in telomere-dysfunctional mice.

There is growing evidence that telomere dysfunction can contribute to human aging. Telomere dysfunction limits lymphopoiesis in aging telomerase knockout (mTerc(-/-)) mice primarily by the induction of stem cell-extrinsic alterations. The relative contribution of alterations in the stem cell niche and the systemic environment to the impairment of lymphopoiesis in response to telomere dysfunction is currently unknown.

Determining the influence of telomere dysfunction and DNA damage on stem and progenitor cell aging: what markers can we use?

The decline in organ maintenance and function is one of the major problems limiting quality of life during aging. The accumulation of telomere dysfunction and DNA damage appears to be one of the underlying causes. Uncapping of chromosome ends in response to critical telomere shortening limits the proliferative capacity of human cells by activation of DNA damage checkpoints inducing senescence or apoptosis.

Proteins induced by telomere dysfunction and DNA damage represent biomarkers of human aging and disease.

Telomere dysfunction limits the proliferative capacity of human cells by activation of DNA damage responses, inducing senescence or apoptosis. In humans, telomere shortening occurs in the vast majority of tissues during aging, and telomere shortening is accelerated in chronic diseases that increase the rate of cell turnover. Yet, the functional role of telomere dysfunction and DNA damage in human aging and diseases remains under debate.

Cell intrinsic and extrinsic mechanisms of stem cell aging depend on telomere status.

The function of adult stem cells declines during aging and chronic diseases. An understanding of the molecular mechanisms underlying these processes will help to identify targets for future therapies in order to improve regenerative reserve and organ maintenance. Telomere shortening represents a cell intrinsic mechanism inducing DNA damage in aging cells.