Journal article
The Role of Telomerase Activity and Telomere Length in Cellular Sensitivity to DNA Damaging Agents
Blood, Vol.108(11), pp.4192-4192
11/16/2006
DOI: 10.1182/blood.V108.11.4192.4192
Abstract
Abstract Dyskeratosis congenita (DC) is a premature aging syndrome characterized by progressive bone marrow failure, abnormal skin pigmentation and nail dystrophy. We have described an autosomal dominant form of DC (AD DC) in a large three-generation kindred that is due to a mutation in the gene encoding human telomerase RNA (hTR). While telomere shortening is a normal consequence of the aging process, DC patients display extremely short telomeres in many somatic cell types, including hematopoietic cells, and they often suffer from bone marrow failure. Allogeneic hematopoietic stem cell transplant (HSCT) remains the only curative therapy for marrow failure in DC. However, HSCT in DC is generally poorly tolerated and associated with significant morbidity, perhaps as a consequence of increased sensitivity of dividing cells to cytotoxic agents during myeloablative therapy. To test this hypothesis, we characterized lymphocytes from various AD DC patients and age matched controls that had been placed in long term culture following in vitro exposure to irradiation (137Cs) and varying doses of Taxol, Adriamycin, and Etoposide. Cell proliferation and viability were quantified by direct visual counting on a hemocytometer, and flow cytometry was employed to assess apoptosis and cell surface expression of senescent markers. In addition to DC lymphocytes having a decreased proliferative capacity and higher basal apoptotic levels, an increased sensitivity to irradiation, Taxol, Adriamycin, and Etoposide was noted. These results suggest that telomere shortening may be an important factor in determining cellular tolerance to cytotoxic therapy and support the concept of reduced intensity HSCT regimens in both aged individuals and DC patients. Further studies have been initiated to determine whether reconstitution of telomere length in DC cells alters response to cytotoxic agents.
Details
- Title: Subtitle
- The Role of Telomerase Activity and Telomere Length in Cellular Sensitivity to DNA Damaging Agents
- Creators
- Greg T Rice - Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, IA, USAMichael A Beasley - Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, IA, USAIke I Akabogu - Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, IA, USAErik R Westin - Program in Genetics, University of Iowa Hospitals and Clinics, Iowa City, IA, USADale A Winnike - Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, IA, USAAloysius J Klingelhutz - Microbiology, University of Iowa Hospitals and Clinics, Iowa City, IA, USAFrederick D Goldman - Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
- Resource Type
- Journal article
- Publication Details
- Blood, Vol.108(11), pp.4192-4192
- DOI
- 10.1182/blood.V108.11.4192.4192
- ISSN
- 0006-4971
- eISSN
- 1528-0020
- Language
- English
- Date published
- 11/16/2006
- Academic Unit
- Radiation Oncology; Microbiology and Immunology
- Record Identifier
- 9984001166902771
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