The partial tandem duplication of ALL1 (MLL) is consistently generated by Alu-mediated homologous recombination in acute myeloid leukemia.

Chromosome abnormalities resulting in gene fusions are commonly associated with acute myeloid leukemia (AML), however, the molecular mechanism(s) responsible for these defects are not well understood. The partial tandem duplication of the ALL1 (MLL) gene is found in patients with AML and trisomy 11 as a sole cytogenetic abnormality and in 11% of patients with AML and normal cytogenetics. This defect results from the genomic fusion of ALL1 intron 6 or intron 8 to ALL1 intron 1. Here, we examined the DNA sequence at the genomic fusion in nine cases of AML with a tandem duplication of ALL1 spanning exons 2-6. Each breakpoint occurred within intron 6 of the ALL1 breakpoint cluster region and within a discrete 3.8-kb region near the 3' end of intron 1. In seven cases, a distinct point of fusion of intron 6 with intron 1 could not be identified. Instead, the sequence gradually diverged from an Alu element in intron 6 to an Alu element in intron 1 through a heteroduplex fusion. Thus, these rearrangements appear to be the result of a recombination event between homologous Alu sequences in introns 6 and 1. In two cases, the genomic junction was distinct and involved the fusion of a portion of an Alu element in intron 6 with non-Alu sequence in intron 1. These data support the hypothesis that a recombination event between homologous Alu sequences is responsible for the partial tandem duplication of ALL1 in the majority of AML cases with this genetic defect. Although Alu element-mediated homologous recombination events in germline cells are thought to be responsible for partial gene duplications or deletions in many inherited diseases, this appears to be the first demonstration identifying Alu element-mediated recombination as a consistent mechanism for gene rearrangement in somatic tissue.