The distribution and accumulation of the shortest telomeres in telomere biology disorders.

Autor: Raj HA; Division of Cancer Epidemiology and Genetics, Clinical Genetics Branch, National Cancer Institute, Rockville, Maryland, USA., Lai TP; Center of Human Development and Aging, Rutgers University of New Jersey, New Jersey Medical School, Newark, New Jersey, USA., Niewisch MR; 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., Giri N; Division of Cancer Epidemiology and Genetics, Clinical Genetics Branch, National Cancer Institute, Rockville, Maryland, USA., Wang Y; Division of Cancer Epidemiology and Genetics, Clinical Genetics Branch, National Cancer Institute, Rockville, Maryland, USA., Spellman SR; Center for International Blood and Marrow Transplant Research, National Marrow Donor Program/Be The Match, Minneapolis, Minnesota, USA., Aviv A; Center of Human Development and Aging, Rutgers University of New Jersey, New Jersey Medical School, Newark, New Jersey, USA., Gadalla SM; Division of Cancer Epidemiology and Genetics, Clinical Genetics Branch, National Cancer Institute, Rockville, Maryland, USA., Savage SA; Division of Cancer Epidemiology and Genetics, Clinical Genetics Branch, National Cancer Institute, Rockville, Maryland, USA.
Jazyk: angličtina
Zdroj: British journal of haematology [Br J Haematol] 2023 Dec; Vol. 203 (5), pp. 820-828. Date of Electronic Publication: 2023 Jun 24.
DOI: 10.1111/bjh.18945
Abstrakt: 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.
(© 2023 British Society for Haematology and John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)
Databáze: MEDLINE
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