Structure and possible mechanisms of TEL-AML1 gene fusions in childhood acute lymphoblastic leukemia

TEL-AML1 gene fusion derived by chromosomal translocation is a common acqui red genetic lesion in pediatric cancer that is present in similar to 25% of B-cell precursor acute lymphoblastic leukemias, and recent evidence sugges ts that this recombination event may initiate leukemogenesis prenatally dur ing fetal hemopoiesis. Analysis of the DNA sequence and structure surroundi ng the breakpoints may reveal clues to their formation. A long-distance inv erse PCR strategy was used to amplify TEL-AML1 genomic fusion sequences fro m diagnostic DNA from nine patients. Breakpoints were scattered within the 14 kb of intronic DNA between exons 5 and 6 of TEL and in two putative clus ter regions within AML1 intron 1, Fusion sequences exhibited characteristic signs of nonhomologous end joining, including microhomologies at the end p oints, and small deletions and duplications, DNA sequences near the breakpo ints did not reveal any consistent characteristic signal sequences of the V (D)J recombinase, topoisomerase II consensus sites, or other sequence moths associated with recombination, However, several translocations occurred ne ar a repeat region of TEL that was found to be highly polymorphic. This reg ion was cloned and found in nuclease sensitivity assays to exhibit paranemi c structures, which may have contributed to DNA breakage or illegitimate re combination, The data are compatible with the possibility that TEL-AML1 tra nslocations occur by nonhomologous recombination involving imprecise, const itutive repair processes following DNA double-strand breaks.