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Fate of Premalignant Clones during the Asymptomatic Phase Preceding Lymphoid Malignancy

¹ Oncovirologie et Biothérapies, UMR5537 CNRS-Université Claude Bernard, Centre Léon Bérard; ² Service d'Hématologie, Pavillon E, Hôpital Edouard Herriot, Place d'Arsonval, Lyon, France; ³ Department of Pathology, National Veterinary Research Institute, Pulawy, Poland; ⁴ Department of Virology, Veterinary, and Agrochemical Research Centre, 1180 Uccle, Belgium; and ⁵ Faculté Universitaire des Sciences Agronomiques, Gembloux, Belgium

Requests for reprints: Eric Watel, Oncovirologie et Biothérapies, UMR5537 CNRS-Université Claude Bernard, Centre Léon Bérard, 28, rue Laënnec, 69373 Lyon cedex 08, France. Phone: 33-4-78-78-26-69; Fax: 33-4-78-78-27-17; E-mail: wattel{at}lyon.fnclcc.fr.

Almost all cancers are preceded by a prolonged period of clinical latency during which a combination of cellular events helps move carcinogen-exposed cells towards a malignant phenotype. Hitherto, investigating the fate of premalignant cells in vivo remained strongly hampered by the fact that these cells are usually indistinguishable from their normal counterparts. Here, for the first time, we have designed a strategy able to reconstitute the replicative history of the bona fide premalignant clone in an animal model, the sheep experimentally infected with the lymphotropic bovine leukemia virus. We have shown that premalignant clones are early and clearly distinguished from other virus-exposed cells on the basis of their degree of clonal expansion and genetic instability. Detectable as early as 0.5 month after the beginning of virus exposure, premalignant cells displayed a two-step pattern of extensive clonal expansion together with a mutation load 6 times higher than that of other virus-exposed cells that remained untransformed during the life span of investigated animals. There was no fixation of somatic mutations over time, suggesting that they regularly lead to cellular death, partly contributing to maintain a normal lymphocyte count during the prolonged premalignant stage. This equilibrium was finally broken after a period of 18.5 to 60 months of clinical latency, when a dramatic decrease in the genetic instability of premalignant cells coincided with a rapid increase in lymphocyte count and lymphoma onset.

Key Words: bovine leukemia virus • Leukemias and lymphomas • Animal models of cancer • Viral organisms and mechanisms • Retroviruses • Viral transformation and carcinogenesis

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