An E mu-BCL-2 transgene facilitates leukaemogenesis by ionizing radiation

Clonogenic murine B cell precursors are normally ultrasensiti ve to apoptos is following genotoxic exposure in vitro but can be protected by expression of an E mu-BCL-2 transgene. Such exposures are likely to be mutagenic. Thi s in turn suggests that a level of in vivo genotoxic exposure that usually has minimal pathological consequences might become leukaemogenic when damag ed cells fail to abort by apoptosis. If this were to be the case, then the cell type that becomes leukaemic and the chromosomal/molecular changes that occur would also be of considerable interest. We tested this possibility b y exposing E mu-BCL-2 and wild-type mice of differing ages to a single dose of X-irradiation of 1-4 Gy, Young (similar to 4-6 weeks) transgenic mice d eveloped leukaemia at a high rate following exposure to 2 Gy but adult mice (4-6 months) did not. Exposure to 4 Gy produced leukaemia in both young an d adult transgenic mice but at a higher frequency in the former. Leukaemic cell populations showed clonal rearrangements of the IGH gene but in most c ases analysed had immunophenotypic features of an early B lympho-myeloid pr ogenitor population which has not previously been recorded in radiation leu kaemogenesis. Molecular cytogenetic analysis of leukaemic cells by banded k aryotype and FISH revealed a consistent double abnormality: trisomy 15 plus an interstitial deletion of chromosome 4 that was confirmed by LOH analysi s.