Evolution of retrovirus-infected premalignant T-cell clones prior to adult T-cell leukemia/lymphoma diagnosis

Aileen G. Rowan, Richard Dillon, Aviva Witkover, Anat Melamed, Maria Antonietta Demontis, Nicolas A. Gillet, Liew Jun Mun, Charles R.M. Bangham, Lucy B. Cook, Paul A. Fields, Graham P. Taylor

Research output: Contribution to journalArticlepeer-review

Abstract

Adult T-cell leukemia/lymphoma (ATL) is an aggressive hematological malignancy caused by human T-cell leukemia virus type-1 (HTLV-1). ATL is preceded by decades of chronic HTLV-1 infection, and the tumors carry both somatic mutations and proviral DNA integrated into the tumor genome. In order to gain insight into the oncogenic process, we used targeted sequencing to track the evolution of the malignant clone in 6 individuals, 2 to 10 years before the diagnosis of ATL. Clones of premalignant HTLV-1-infected cells bearing known driver mutations were detected in the blood up to 10 years before individuals developed acute and lymphoma subtype ATL. Six months before diagnosis, the total number and variant allele fraction of mutations increased in the blood. Peripheral blood mononuclear cells from premalignant cases (1 year prediagnosis) had significantly higher mutational burden in genes frequently mutated in ATL than did high-risk, age-matched HTLV-1 carriers who remained ATL-free after a median of 10 years of follow-up. These data show that HTLV-1-infected T-cell clones carrying key oncogenic driver mutations can be detected in cases of ATL years before the onset of symptoms. Early detection of such mutations may enable earlier and more effective intervention to prevent the development of ATL.

Original languageEnglish
Pages (from-to)2023-2032
Number of pages10
JournalBlood
Volume135
Issue number23
DOIs
Publication statusPublished - 4 Jun 2020
Externally publishedYes

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