Telomere dynamics in childhood leukemia and solid tumors: a follow-up study

Franco, Sonia; Özkaynak, M. Fevzi; Sandoval, Claudio; Tugal, Oya; Jayabose, Somasundaram; Engelhardt, Monika; Moore, Malcolm A.S.

doi:10.1038/sj.leu.2402815

Cited by 42 publications

(39 citation statements)

References 65 publications

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“…In numerous hematologic disorders, a significant mean TRF reduction is seen in patients versus age-matched controls in peripheral blood mononuclear cells (5,20,24,25). In studies where telomere length was measured in the PBMCs of solid tumor patients that receive more intensive treatment protocols, greater telomere shortening was seen per unit time than in leukemia patients where less intensive treatment protocols were employed (20). Our linear regression analysis results suggest that no mean TRF difference is seen in locally advanced head and neck cancer patients at diagnosis compared with individuals without cancer, suggesting that cancer itself does not alter telomere length in PBMCs.…”

Section: Discussionmentioning

confidence: 99%

“…The authors attribute the large reduction to increased proliferative stress of stem cells undergoing two consecutive treatments. In a separate study, combination chemotherapy was given to 24 pediatric patients with acute lymphoblastic leukemia and solid tumors (20,22). In acute lymphoblastic leukemia patients, the rates of attrition in lymphocytes and granulocytes were 480 and 360 bp/y, respectively.…”

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confidence: 99%

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Acceleration of Telomere Loss by Chemotherapy Is Greater in Older Patients with Locally Advanced Head and Neck Cancer

Unryn

Hao

Glück

et al. 2006

Clinical Cancer Research

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Purpose: Chronic viral infection and combinations of chemotherapeutic drugs have been reported to accelerate telomere erosion. Here, we asked if chemoradiotherapy, using the single agent cisplatin, would accelerate telomere loss in head and neck cancer patients, and whether loss was linked to smoking status, age, gender, or stage of disease at diagnosis. Experimental Design: Blood samples were collected from 20 patients with squamous cell cancer of the head and neck before, during, and after chemoradiotherapy. Following DNA isolation from peripheral blood mononuclear cells, telomere length was measured by terminal restriction fragment analysis.Results: Chemoradiotherapy increased the rate of telomere erosion >100-fold. Telomere length before treatment in chemoradiotherapy patients was similar to age-matched controls. Although smokers began with significantly shorter telomeres, smoking status did not affect chemoradiotherapy-induced attrition, nor did gender or stage of disease.We also make the novel observation that a significantly greater telomere loss occurred in response to treatment in older patients, with those younger than 55 years losing an average of 400 bp of telomeric DNA compared with the 880 bp lost by those over 55 years. Conclusions: The lack of telomere length difference before treatment suggests that shortened telomeres may not be a risk factor for development of head and neck cancer in the age range we examined. Chemoradiotherapy caused a severe telomere length reduction in all patients. The significant difference seen in the elderly (P = 0.018) suggests that chemoradiotherapy may have more severe effects on the replicative capacity of blood cells in older patients.Eukaryotic chromosome ends consist of specialized structures called telomeres that are critical to chromosome integrity. In vertebrates, the DNA component of telomeres consists of the hexamer T 2 AG 3 repeated thousands of times. Attrition of these repeats occurs as cells divide, primarily due to the endreplication problem and to the accumulation of oxidative damage within telomeric DNA (1, 2). The concept that telomeres represent cellular ''clocks'' for predicting proliferative potential and limiting proliferative life span (3) reinforces the importance of examining situations in which unusually rapid shortening might occur. Under normal circumstances, the rate of lymphocyte telomere loss in vivo varies between 15 and 55 bp per year in adults (4) with more rapid losses seen earlier in life. Various disease states and chronic stresses, such as Down's syndrome and HIV infection, significantly accelerate the loss of telomeric DNA in lymphocytes. Viral infection can increase losses by >5-fold (5 -8), resulting in premature senescence of the immune system (9) from which patients do not fully recover.Randomized controlled clinical trials have shown that concurrent chemoradiotherapy confers a survival benefit over radiation alone in patients with locally advanced head and neck cancer (10). Although the optimal concurrent chemothera...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Acceleration of Telomere Loss by Chemotherapy Is Greater in Older Patients with Locally Advanced Head and Neck Cancer

Unryn

Hao

Glück

et al. 2006

Clinical Cancer Research

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“…The contribution of telomere shortening to the cytogenetic abnormalities commonly seen in leukemia is an active area of investigation; many of these studies have been reviewed in detail by others (Deville et al 2006;Drummond et al 2007). The majority of these studies were performed on pre-therapeutic specimens, but it should be noted that cytotoxic chemotherapy can also contribute to telomere shortening (Fern et al 2004;Franco et al 2003).…”

Section: Hematopoietic Malignanciesmentioning

confidence: 99%

The role of telomere biology in bone marrow failure and other disorders

Savage

Alter

2008

Mechanisms of Ageing and Development

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Telomeres, consisting of nucleotide repeats and a protein complex at chromosome ends, are essential in maintaining chromosomal integrity. Dyskeratosis congenita (DC) is the inherited bone marrow failure syndrome (IBMFS) that epitomizes the effects of abnormal telomere biology. Patients with DC have extremely short telomere lengths (<1 st percentile) and many have mutations in telomere biology genes. Interpretation of telomere length in other IBMFSs is less straightforward. Abnormal telomere shortening has been reported in patients with apparently acquired hematologic disorders, including aplastic anemia, myeolodysplasia, paroxysmal nocturnal hemoglobinuria, and leukemia. In these disorders, the shortest lived cells have the shortest telomeres, suggestive of increased hematopoietic stress. Telomeres are also markers of replicative and/or oxidative stress in other complex disease pathways, such as inflammation, stress, and carcinogenesis.The spectrum of related disorders caused by mutations in telomere biology genes extends beyond classical DC to include marrow failure that does not respond to immunosuppression, idiopathic pulmonary fibrosis, and possibly other syndromes. We suggest that such patients are categorized as having an inherited disorder of telomere biology. Longitudinal studies of patients with very short telomeres but without classical DC are necessary to further understand the long-term sequelae, such as malignancy, osteonecrosis/osteoporosis, and pulmonary and liver disease.

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“…Three studies investigated TA during the course of disease and correlations between enzyme activity and response to therapy were found. [4][5][6] Likewise, a reduction of telomere length could be observed during treatment. 4,5 Our results indicate that longitudinal analysis of TA and TRF in long-term studies would be needed to investigate the impact of changes in TA and telomere length during course of disease and its treatment in children with T-ALL.…”

Section: Telomeres and Telomerase In Paediatric Patients With T-cell mentioning

confidence: 83%

“…[4][5][6] Likewise, a reduction of telomere length could be observed during treatment. 4,5 Our results indicate that longitudinal analysis of TA and TRF in long-term studies would be needed to investigate the impact of changes in TA and telomere length during course of disease and its treatment in children with T-ALL. We are aware that our results are based on a relative small number of patients and that interpretation of the results might be therefore somewhat limited.…”

Section: Telomeres and Telomerase In Paediatric Patients With T-cell mentioning

confidence: 83%

Telomeres and telomerase in paediatric patients with T-cell acute lymphoblastic leukaemia (T-ALL)

et al. 2004

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Telomere dynamics in childhood leukemia and solid tumors: a follow-up study

Cited by 42 publications

References 65 publications

Acceleration of Telomere Loss by Chemotherapy Is Greater in Older Patients with Locally Advanced Head and Neck Cancer

Acceleration of Telomere Loss by Chemotherapy Is Greater in Older Patients with Locally Advanced Head and Neck Cancer

The role of telomere biology in bone marrow failure and other disorders

Telomeres and telomerase in paediatric patients with T-cell acute lymphoblastic leukaemia (T-ALL)

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