Microclustering of TEL-AML1 translocation breakpoints in childhood acute lymphoblastic leukemia

TEL-AML1 fusions are the most common chromosome translocations in childhood leukemia and often, if not always, occur in utero. We previously reported the genomic sequencing of nine TEL-AML1 translocations and showed unique st ructural features of a breakpoint cluster region in TEL intron 5. We now re port data on sequencing and mapping of TEL-AML1 from an additional 11 patie nts and, using Monte Carlo statistical methods, have analyzed the intronic distribution of the 24 TEL-AML1 fusion junctions sequenced to date. Compare d to a null hypothesis of random breakpoint allocation within TEL intron 5 and AML1 introns 1 and 2, significant microclustering was evident on both T EL and AML1. In contrast to previous reports, the two strongest microcluste rs on TEL were 3' to an unstable repeat region. AML1 demonstrated four high ly significant microclusters, two Of which were proximal to exons. We note the necessity of sequencing multiple breakpoints before the description of putative microcluster regions. TEL-AML1 breakpoints may be distributed into microclusters because of specific DNA sequence or chromatin features in su sceptible cells. We also report on additional features of breakpoints, incl uding a complex t(12;3;21) in one patient and an inverted sequence in anoth er. (C) 2000 Wiley-Liss, Inc.