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Guarnera, L.* ; Wahida, A. ; Gurnari, C.* ; Hutter, S.* ; Stainczyk, S.A.* ; Williams, N.* ; Durmaz, A.* ; Kubota, Y.* ; Bravo-Perez, C.* ; Kawashima, N.* ; Orland, M.D.* ; Pagliuca, S.* ; Huang, Y.* ; LaFramboise, T.* ; Visconte, V.* ; Walter, W.* ; Meggendorfer, M.* ; Kern, W.* ; Westermann, F.* ; Feuerbach, L.* ; Haferlach, T.* ; Maciejewski, J.P.*

Determining telomere content and genomics of myeloid neoplasia by whole-genome sequencing.

Blood, DOI: 10.1182/blood.2025028644 (2025)
Postprint Forschungsdaten DOI PMC
Open Access Green
Telomere length shortening has been associated with genomic instability and acquisition of molecular lesions, but these processes have not been systematically studied across large cohorts of myeloid neoplasia (MN). As proof of concept for a novel, cross-validated WGS-based method of telomere content (TC) determination combined with mutations, transcriptomics, and functional assays, we studied TC in correlation with specific molecular features of a large cohort (n=1804) of MN patients including acute myeloid leukemia (AML) and myelodysplastic syndrome. When compared to healthy subjects and patients with non-clonal diseases such as persistent polyclonal B cell lymphocytosis, both MN and non-malignant controls with clonal disease, such as paroxysmal nocturnal hemoglobinuria and aplastic anemia, exhibited decreased TC. Furthermore, we show that TC is lowered in adult MN abrogating correlation with age with considerable TC diversification among certain morphologic and molecular subtypes. For instance, AML harbored the lowest TC. Furthermore, MN originating from a more mature cell of origin (e.g., APL), and those characterized by hyperproliferative driver mutations (e.g., RAS pathway genes) had lower TC, possibly indicating a loss of telomere maintenance capacity. In contrast, MN subtypes arising in a context of profound genetic alterations, such as TP53 mutations and complex karyotype, exhibited a relatively higher/preserved TC compared to other mutations. This phenomenon did not involve alternative lengthening processes but was rather consistent with an increased TC due to preserved activity of the telomerase complex. Our results describe a common and genotype-specific telomeric make-up of a large cohort of patients with MN providing a molecular benchmark for future therapeutic targeting of the telomere machinery.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Sprache englisch
Veröffentlichungsjahr 2025
HGF-Berichtsjahr 2025
ISSN (print) / ISBN 0006-4971
e-ISSN 1528-0020
Zeitschrift Blood
Verlag American Society of Hematology
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Metabolism and Cell Death (MCD)
POF Topic(s) 30203 - Molecular Targets and Therapies
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-506900-001
DOI 10.1182/blood.2025028644
PubMed ID 40983034
Erfassungsdatum 2025-10-21
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