Journal
BLOOD
Volume 123, Issue 25, Pages 3925-3931Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2014-02-553602
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Funding
- Leukaemia and Lymphoma Research
- Wellcome Trust
- MRC [MR/K019090/1] Funding Source: UKRI
- Medical Research Council [MR/K019090/1] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [221S0001, 22114003] Funding Source: KAKEN
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(A)dult T-cell leukemia/lymphoma(ATL) occurs in similar to 5% of human T-lymphotropic virus type 1 (HTLV-1)-infected individuals and is conventionally thought to be a monoclonal disease in which a single HTLV-1(+) T-cell clone progressively outcompetes others and undergoes malignant transformation. Here, using a sensitive high-throughput method, we quantified clonality in 197 ATL cases, identified genomic characteristics of the proviral integration sites in malignant and nonmalignant clones, and investigated the proviral features (genomic structure and 5 ' long terminal repeat methylation) that determine its capacity to express the HTLV-1 oncoprotein Tax. Of the dominant, presumed malignant clones, 91% contained a single provirus. The genomic characteristics of the integration sites in the ATL clones resembled those of the frequent low-abundance clones (present in both ATL cases and carriers) and not those of the intermediate-abundance clones observed in 24% of ATL cases, suggesting that oligoclonal proliferation per se does not cause malignant transformation. Gene ontology analysis revealed an association in 6% of cases between ATL and integration near host genes in 3 functional categories, including genes previously implicated in hematologic malignancies. In all cases of HTLV-1 infection, regardless of ATL, there was evidence of preferential survival of the provirus in vivo in acrocentric chromosomes (13, 14, 15, 21, and 22).
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