Long Telomeres Raise Lymphoma Risk in POT1 Carriers

Researchers at the Johns Hopkins Kimmel Cancer Center and the Telomere Clinic at Johns Hopkins identified an inherited syndrome in which unusually long telomeres keep immune cells biologically younger for longer than normal, increasing the risk of lymphoma and other cancers. The study, published in Blood, links loss-of-function mutations in the POT1 gene to disrupted lymphocyte aging and a greater chance that these long-lived cells will collect cancer-associated mutations over time.

POT1 normally helps control telomere length. When one copy of the gene is inactivated, telomeres can become excessively long. The new work shows that in this inherited setting, that extended cellular lifespan is not simply protective; it may instead create conditions that raise blood cancer risk. Among 51 people from 24 families with POT1 variants, the most common cancers after melanoma were hematologic malignancies and thyroid cancer. Three-quarters of the blood cancers arose from lymphocytes, the immune cells that help fight infection.

The pattern within families was notable. Senior author Mary Armanios explained, “The spectrum of lymphoid cancers was striking,” and described childhood leukemia, multiple lymphoma types, and adult-onset chronic lymphocytic leukemia appearing across generations. She added that some people developed melanoma before lymphoma, while others had as many as five cancers over a lifetime. She also noted that the cancers tended to be slow-growing and usually curable.

The findings extended beyond these families. In the UK Biobank, which included nearly 500,000 people, 210 adults with POT1 variants had an eightfold higher risk of lymphoma, and 45% developed a lymphoid cancer by age 80. In people who had not yet been diagnosed with lymphoma, the researchers found evidence of early lymphocyte clonality, a slow-growing precursor state. After age 60, nearly all POT1 mutation carriers showed expanded lymphocyte clones, and most carried mutations commonly linked to lymphoma.

The study also found that telomere behavior in these cells differed from the normal aging pattern. Instead of shortening with age, telomere length in lymphocytes from POT1 carriers remained stable and sometimes appeared to lengthen. The researchers also observed rarer slow-growing myeloid blood cancers, sometimes alongside lymphoma in the same person.

Armanios said, “Our findings point to a new mechanism of lymphoma susceptibility that is linked to extended cellular longevity.” She added, “Our data suggest that, for now, telomere length clinical testing should be reserved for individuals with variants in the gene that have unclear significance.”