ETV6-AML1 translocation breakpoints cluster near a purine/pyrimidine repeat region in the ETV6 gene

The t(12;21)(p13;q22) translocation, fusing the ETV6 and AML I genes, is th e most frequent chromosomal translocation associated with pediatric B-cell precursor acute lymphoblastic leukemia. Although the genomic organization o f the ETV6 gene and a breakpoint cluster region (bcr) in ETV6 intron 5 has been described, mapping of AML1 breakpoints has been hampered because of th e large, hitherto unknown size of AML1 intron 1, Here, we report the mappin g of the AML1 gene between exons 1 and 3, cloning of ETV6-AML1 breakpoints from different patients, and localization of the AML1 breakpoints within AM L1 intron 1. In contrast to the tightly clustered ETV6 breakpoints, the AML 1 breakpoints were found to be dispersed throughout AML7 intron 1. Although nucleotide sequence analysis of the breakpoint junctions showed several 5/ 7 matches for the V(D)J consensus heptamer recognition sequence, these matc hes were present only on the ETV6 alleles and not on the AML1 alleles, maki ng it unlikely that the translocations were mediated by a simple V(D)J reco mbination mistake. Interestingly, several breakpoints as well as a stable i nsertion polymorphism mapped close to a polymorphic, alternating purine-pyr imidine tract in the ETV6 gene, suggesting that this region may be prone to DNA recombination events such as insertions or translocations. Finally, th e presence of an insertional polymorphism within the ETV6 bcr must be recog nized to avoid incorrect genotype designation based on Southern blot analys is. (C) 1999 by The American Society of Hematology.