Telomere content and genomics of myeloid neoplasia by whole-genome sequencing

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.

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Publication Details

Journal
Blood
Published
2025-09-22
DOI
https://doi.org/10.1182/blood.2025028644
Citations
2
Primary Topic
Telomeres, Telomerase, and Senescence
Type
article
Field-Weighted Citation Impact
2.33

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Telomere content and genomics of myeloid neoplasia by whole-genome sequencing

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Telomere content and genomics of myeloid neoplasia by whole-genome sequencing

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article en
2 citations

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.

BloodVol. 147(2)
University of Rome Tor Vergata (IT), Cleveland Clinic (US), German Cancer Research Center (DE), Heidelberg University (DE), Helmholtz Zentrum München (DE), Munich Leukemia Laboratory (Germany) (DE), European University of Rome (IT), Centre Hospitalier Régional et Universitaire de Nancy (FR), Centre d’Investigation Clinique Innovation Technologique de Nancy (FR), University of Tokyo Hospital (JP), Hopp Children's Cancer Center Heidelberg (DE), Instituto Murciano de Investigación Biosanitaria (ES), Ingénierie Moléculaire et Physiopathologie Articulaire (FR), Case Western Reserve University (US)
Edward P. Evans Foundation, Instituto de Salud Carlos III
Openalex Percentile: Top 10%
Telomeres, Telomerase, and Senescence
2.33
DOIOpen Access PDFOpenAlex
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