Partial tandem duplication of the ALL1 gene in acute myeloid leukemia

Cytogenetically detectable translocations and deletions involving chromosome 11, band q23, account for approximately 5 to 10% of patients with de novo AML. These abnormalities often result in the disruption of a gene at 11q23 known as ALL1. In cases of AML with +11 or normal cytogenetics, we have previously described a cytogenetically undetectable defect involving ALL1 which results in the tandem duplication of an internal portion of the gene spanning exons 2 through 6 or 2 through 8. To test the hypothesis that the partial tandem duplication of ALL1 is a recurrent molecular defect in AML with +11, an analysis of the ALL1 gene was performed in 17 cases of AML and one case of MDS with +11 or +11q, but without cytogenetic evidence of a structural abnormality involving 11q23. Ten of 11 patients (91%) with +11 as a sole abnormality and two of seven patients (29%) with +11 and other aberrations had rearrangement of ALL1. In 10 of the 12 patients, material was available for additional analysis and a partial tandem duplication of ALL1 was detected in each case. The finding of the ALL1 duplication as a recurrent defect in patients with +11 represents the first identification of a specific gene rearrangement associated with recurrent trisomy in human cancer. To test the hypothesis that the partial tandem duplication of ALL1 is a recurrent molecular defect in AML with normal cytogenetics, an analysis of ALL1 gene rearrangement was performed in 98 patients with AML and normal cytogenetics. Eleven cases (11%) showed rearrangement of ALL1 by Southern analysis. A partial tandem duplication of ALL1 was diagnosed in nine of the 11 cases with adequate material. Further, when compared with patients without rearrangement of ALL1, patients with a rearranged ALL1 had a significantly shortened duration of CR. Molecular analysis of allelic dosage revealed that the partial tandem duplication of ALL1 is found on a single chromosome, regardless of whether the karyotype of AML blasts is normal or displays +11 as a sole cytogenetic abnormality, demonstrating that a single mutated ALL1 allele with the partial duplication is sufficient for ALL1-associated leukemogenesis. Sequence analysis of the genomic breakpoints in nine cases of AML with tandem duplication of ALL1 spanning exons 2 through 6 revealed that the molecular mechanism responsible for this defect involves a recombination event between homologous Alu elements in introns 6 and 1.