The distribution and accumulation of the shortest telomeres in telomere biology disorders |
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Authors: | Hannah A Raj Tsung-Po Lai Marena R Niewisch Neelam Giri Youjin Wang Stephen R Spellman Abraham Aviv Shahinaz M Gadalla Sharon A Savage |
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Institution: | 1. Division of Cancer Epidemiology and Genetics, Clinical Genetics Branch, National Cancer Institute, Rockville, Maryland, USA;2. Center of Human Development and Aging, Rutgers University of New Jersey, New Jersey Medical School, Newark, New Jersey, USA;3. Division of Cancer Epidemiology and Genetics, Clinical Genetics Branch, National Cancer Institute, Rockville, Maryland, USA
Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany;4. Center for International Blood and Marrow Transplant Research, National Marrow Donor Program/Be The Match, Minneapolis, Minnesota, USA |
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Abstract: | Individuals with telomere biology disorders (TBDs) have very short telomeres, high risk of bone marrow failure (BMF), and reduced survival. Using data from TBD patients, a mean leukocyte Southern blot telomere length (TL) of 5 kilobases (kb) was estimated as the ‘telomere brink’ at which human survival is markedly reduced. However, the shortest telomere, not the mean TL, signals replicative senescence. We used the Telomere Shortest Length Assay (TeSLA) to tally TL of all 46 chromosomes in blood-derived DNA and examined its relationship with TBDs. Patients (n = 18) had much shorter mean TL (TeSmTL) (2.54 ± 0.41 kb vs. 4.48 ± 0.52 kb, p < 0.0001) and more telomeres <3 kb than controls (n = 22) (70.43 ± 8.76% vs. 33.05 ± 6.93%, p < 0.0001). The proportion of ultrashort telomeres (<1.6 kb) was also higher in patients than controls (39.29 ± 10.69% vs. 10.40 ± 4.09%, p < 0.0001). TeS <1.6 kb was associated with severe (n = 11) compared with non-severe (n = 7) BMF (p = 0.027). Patients with multi-organ manifestations (n = 10) had more telomeres <1.6 kb than those with one affected organ system (n = 8) (p = 0.029). Findings suggest that TBD clinical manifestations are associated with a disproportionately higher number of haematopoietic cell telomeres reaching a telomere brink, whose length at the single telomere level is yet to be determined. |
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Keywords: | bone marrow failure dyskeratosis congenita telomere telomere biology disorder telomere length TeSLA |
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