Molecular analysis of the genomic inversion and insertion of AF10 into MLLsuggests a single-step event

The interstitial insertion of genetic material from one chromosome into ano ther can achieve the type of gene-gene fusions more usually associated with chromosome translocations. An example of such an interstitial insertion, w hich has created an MLL-AF10 fusion in an acute myeloid leukaemia, has been analysed at the genomic level. The genomic fusion, which resulted in the j uxtaposition of 3' AF10 sequence to 5' MLL sequence, was identified within MLL and AF10 intronic sequences. It was further established that the remain ing 3' MLL sequence, from exon 6 onwards, was fused to novel sequence of un known origin (named FM3 for fused to MLL 3'). The points of fusion of these 5' and 3' portions of MLL matched to adjacent nucleotides and lay between exons 5 and 6. The FM3 sequence was shown to be from chromosome arm 10p and located close to AF10 in a proximal position. It was subsequently demonstr ated that in the leukaemia a third fusion existed between 5' AF10 and the F M3 sequence at a point immediately downstream from its fusion to MLL. It wa s therefore concluded that the MLL-AF10 gene fusion is the result of a simu ltaneous transposition of genetic material into the MLL gene and the joinin g of the remaining free ends on chromosome 10. This kind of event, characte rised completely here for the first time, is a means to achieve a fusion wh en the genes involved lie in opposite orientations and results in three gen omic junctions. (C) 2001 Wiley-Liss, Inc.