The Molecular Biology of Radiation-induced Carcinogenesis: Thymic Lymphoma, Myeloid Leukaemia and Osteosarcoma

Abstract

In mice, external X- or gamma-irradiation may induce thymic lymphomas or myeloid leukaemias, while bone-seeking alpha-emitters may induce osteosarcomas and, to a lesser extent, acute myeloid leukaemia. The present paper aims to review briefly some of the experimental data with respect to the molecular mechanisms underlying these radiation-induced carcinogenic processes. Thymic lymphomagenesis proceeds through an indirect mechanism. Recombinant proviruses often occur in the tumour cell DNA, favouring the idea that they might be involved. However, there are indications that they might mediate tumour growth rather than induction. It is plausible that activation of ras oncogenes by somatic point mutations might play a role in the carcinogenic process, although at a yet undetermined stage. Myeloid leukaemogenesis is characterized by a very early, putative initiating event, consisting of non-random rearrangements and/or deletions of chromosome 2. These may be related to deletions in the developmentally important homeobox gene clusters and to rearrangements of the sequences flanking the IL-1 beta gene. Either a gene of the homeobox family or IL-1 beta might be considered as potentially involved in the induction process. Osteosarcomagenesis in mice is often associated with the expression of proviruses, and the tumours often contain somatically acquired proviruses. These viruses may contribute to tumour development by affecting various growth-suppressor genes. Viruses isolated from bone tumours, although non-sarcomagenic, induce osteopetrosis, osteomas and lymphomas upon infection of newborn mice. Osteogenic tumours frequently display amplification of a region on mouse chromosome 15, which encompasses c-myc and Mlvi-1 sequences. Enhanced transcription of various oncogenes is found in individual tumours, but no specificity for osteosarcomas has been identified. In vitro systems of skeletoblast differentiation are being developed to study tumour induction in vitro.