Ionizing radiation and leukaemia: more questions than answers.

The mechanisms underlying the unequivocal association between ionizing radiation and the development of leukaemia remain unknown. Recent progress in defining sub-cellular events has contributed to our understanding of the production of genetic lesions in irradiated cells but the importance of tissue effects in response to radiation damage has attracted much less attention. Thus, genetic lesions induced by radiation are considered to result from the deposition of energy in the cell nucleus and the initiating lesion for radiation-induced transformation has been similarly attributed to direct DNA damage. Recently, however, there have been many reports of radiation effects, characteristically associated with the consequences of energy deposition in the cell nucleus, arising in non-irradiated cells as a consequence of communication with irradiated cells. These, so-called, non-targeted radiation effects pose major challenges to current views of the mechanisms of radiation-induced DNA damage and the mechanisms underlying radiogenic malignancies. Considered together with data obtained from laboratory model systems, a rather complex picture of radiation leukaemogenesis is emerging in which, additional to any damage induced directly in target stem cells, the haemopoietic microenvironment can be a source of damaging signals and cellular interactions make important genotype-dependent contributions to determining overall outcome after radiation exposures.