Short telomeres result in chromosomal instability in hematopoietic cells and precede malignant evolution in human aplastic anemia
| Autor: | Hesed Padilla-Nash, Phillip Scheinberg, James N. Cooper, Elaine M. Sloand, Rodrigo T. Calado, Colin O. Wu, Neal S. Young, Thomas Ried |
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| Rok vydání: | 2011 |
| Předmět: |
Adult
Male Cancer Research Telomerase Adolescent Hematopoietic System Clone (cell biology) Biology medicine.disease_cause Article Malignant transformation Chromosomal Instability Chromosome instability medicine Humans Aplastic anemia Child HEMATOPOESE (METABOLISMO) Telomere Shortening Aged Aged 80 and over Anemia Aplastic Hematology Middle Aged Aneuploidy medicine.disease Telomere Cell Transformation Neoplastic medicine.anatomical_structure Oncology Child Preschool Immunology Female Bone marrow Carcinogenesis |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| ISSN: | 1476-5551 0887-6924 |
| Popis: | In cell and animal models, telomere erosion promotes chromosomal instability via breakage-fusion-bridge cycles, contributing to the early stages of tumorigenesis. However, evidence involving short telomeres in cancer development in humans is scarce, epidemiologic, and indirect. Here we directly implicate telomere shortening as a critical molecular event for malignant evolution in aplastic anemia. Patients’ telomere lengths at diagnosis of aplastic anemia, while comparable to age-matched controls, inversely correlated with the probability of developing a cytogenetically abnormal clone. A significantly increased number of telomere signal-free chromosomal ends and chromosomal numerical and structural abnormalities were observed in bone marrow cells of patients with shorter telomeres in comparison to patients with longer telomeres and healthy subjects. The proportion of monosomy 7 cells in the bone marrow at diagnosis of aplastic anemia inversely correlated with telomere length, years before the emergence of an autonomous and clinically detectable abnormal clone. Marrow cells of clinically healthy individuals carrying loss-of-function telomerase mutations and with extremely short telomeres also showed chromosomal instability in vitro. These results provide the first clinical direct evidence in humans that short telomeres in hematopoietic cells are dysfunctional, mediate chromosomal instability, and predispose to malignant transformation in a human disease. |
| Databáze: | OpenAIRE |
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