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 structural features of a breakpoint cluster region in TEL intron 5. We now report data on sequencing and mapping of TEL-AML1 from an additional 11 patients and, using Monte Carlo statistical methods, have analyzed the intronic distribution of the 24 TEL-AML1 fusion junctions sequenced to date. Compared to a null hypothesis of random breakpoint allocation within TEL intron 5 and AML1 introns 1 and 2, significant microclustering was evident on both TEL and AML1. In contrast to previous reports, the two strongest microclusters on TEL were 3' to an unstable repeat region. AML1 demonstrated four highly 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 susceptible cells. We also report on additional features of breakpoints, including a complex t(12;3;21) in one patient and an inverted sequence in another.
Wiemels
J L
JL
Leukaemia Research Fund Centre, Institute of Cancer Research, London, UK. jwiemels@epi.ucsf.edu
Alexander
F E
FE
Cazzaniga
G
G
Biondi
A
A
Mayer
S P
SP
Greaves
M
M
D001483:Base Sequence; D002648:Child; D019457:Chromosome Breakage / Q000235:genetics*; D050676:Core Binding Factor Alpha 2 Subunit; D006801:Humans; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D014178:Translocation, Genetic / Q000235:genetics*; D000097764:ETS Translocation Variant 6 Protein
D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein