Year: 2025
Type: article
Study design: Observational Study
Abstract: ABSTRACT: 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 whole-genome sequencing-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 patients with MN, including acute myeloid leukemia (AML) and myelodysplastic syndrome. When compared with healthy participants and patients with nonclonal diseases such as persistent polyclonal B-cell lymphocytosis, both MN and nonmalignant 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 (eg, acute promyelocytic leukemia) or characterized by hyperproliferative driver mutations (eg, RAS pathway genes) had lower TC, possibly indicating a loss of telomere maintenance capacity. In contrast, compared with other mutations, MN subtypes arising in a context of profound genetic alterations, such as TP53 mutations and complex karyotype, exhibited a relatively higher/preserved TC. 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 makeup of a large cohort of patients with MN providing a molecular benchmark for future therapeutic targeting of the telomere machinery.
Source: Blood
Authors: Luca Guarnera, Adam Wahida, Carmelo Gurnari, Stephan Hutter, Sabine A. Stainczyk, Nakisha D. Williams, Arda Durmaz, Yasuo Kubota, Carlos Bravo-Perez, Naomi Kawashima, Mark Orland, Simona Pagliuca, Yimin Huang, Thomas LaFramboise, Valeria Visconte, Wencke Walter, Manja Meggendorfer, Wolfgang Kern, Frank Westermann, Lars Feuerbach, Torsten Haferlach, Jaroslaw P. Maciejewski
Institutions: University of Rome Tor Vergata, Cleveland Clinic, Sapienza University of Rome, Helmholtz Munich, Munich Leukemia Laboratory (Germany), German Cancer Research Center, Hopp Children's Cancer Center Heidelberg, University of Tokyo Hospital, The University of Tokyo, Instituto de Salud Carlos III, Hospital General Universitario Morales Meseguer, Instituto Murciano de Investigación Biosanitaria, Universidad de Murcia, Centre National de la Recherche Scientifique, Centre Hospitalier Régional et Universitaire de Nancy, Ingénierie Moléculaire, Cellulaire et Physiopathologie, Université de Lorraine, Case Western Reserve University, Deutsches Konsortium für Translationale Krebsforschung
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,500
OpenAlex ID: W4414397663