| Title: | Lymphoid malignancy and clonality in the POT1-mediated long telomere syndrome |
| Journal: | Blood |
| Published: | 23 Jan 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41564438/ |
| DOI: | https://doi.org/10.1182/blood.2025031287 |
| URL: | https://pubmed.ncbi.nlm.nih.gov/41564438/ |
Publication 20222
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Abstract
ABSTRACT: Long telomere length (TL) extends replicative capacity in vitro and predisposes to clonal hematopoiesis. We characterized the cancer phenotype in 51 individuals from 24 families with mutant POT1, a negative regulator of telomerase elongation (median age, 51 years [range, 5-94]). Hematologic malignancies were second in prevalence after melanoma (27%), and lymphoid subsets were more common. They clustered with history of sarcoma, thyroid cancer, and chronic myeloproliferative neoplasms. UK Biobank participants with pathogenic POT1 variants had long TL and higher lymphoid malignancy rates (45% by the age of 80 years; hazard ratio, 8.28; 95% confidence interval, 5.29-13.0). Across cohorts, diagnoses encompassed acute lymphoblastic leukemia and Hodgkin lymphoma in children/young adults and chronic lymphocytic leukemia/multiple myeloma in adults. They clustered in families manifesting as autosomal dominant pan-lymphoma with genetic anticipation at times. Lymphocyte TL was longer than granulocytes at baseline (age-adjusted mean +1 kilobase; P< .0001) and was preserved longitudinally with aging. Ultralong lymphocyte TL >99th percentile was more sensitive for identifying pathogenic variants (58% vs 38% for granulocytes). Among asymptomatic POT1 variant carriers, 12 of 20 (60%) had immunophenotype-detected B- and/or T-cell clonality, with complete penetrance after the age of 65 years (7/7). IGH CDR3 sequencing supported age-dependent pruning of the B-cell repertoire, and cytogenetic and next-generation analyses uncovered preclinical clonal lymphoma-associated changes in nearly all POT1 variant carriers aged >60 years (9/10). Our data identify extended cellular longevity due to long TL as an inherited risk factor for lymphoma, explaining its syndromic association with solid tumors and, in some cases, myeloproliferative neoplasms.</p>
17 Keywords
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Child
- Child, Preschool
- Female
- Humans
- Lymphoma
- Male
- Middle Aged
- Mutation
- Shelterin Complex
- Telomere
- Telomere Homeostasis
- Telomere-Binding Proteins
- Young Adult
13 Authors
- Hannah R. Davidson-Swinton
- Sheila Iyer
- Anna Kolchinski
- Jasmine A. Salem
- Emily A. DeBoy
- Andrew G. Kilada
- Jisoo S. Hwang
- Tania Jain
- Siobán B. Keel
- Christopher D. Gocke
- Ying S. Zou
- Kristen E. Schratz
- Mary Armanios
1 Application
| Application ID | Title |
|---|---|
| 17731 | A phenome-wide association study of copy number variation |
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