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

TY - JOUR

T1 - Evolution of retrovirus-infected premalignant T-cell clones prior to Adult T-cell leukemia/lymphoma diagnosis

AU - Rowan, Aileen G

AU - Dillon, Richard

AU - Witkover, Aviva

AU - Melamed, Anat

AU - Demontis, Maria-Antonietta

AU - Gillet, Nicolas Albert

AU - Mun, Liew Jun

AU - Bangham, Charles R M

AU - Cook, Lucy B

AU - Fields, Paul A

AU - Taylor, Graham P

N1 - Copyright © 2020 American Society of Hematology.

PY - 2020/6/4

Y1 - 2020/6/4

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85086480607

U2 - 10.1182/blood.2019002665

DO - 10.1182/blood.2019002665

M3 - Article

C2 - 32160278

SN - 0006-4971

VL - 135

SP - 2023

EP - 2032

JO - Blood

JF - Blood

IS - 23

ER -