ETV6-AML1 Translocation Breakpoints Cluster Near a Purine/Pyrimidine Repeat Region in the ETV6 Gene

Abstract

The t(12;21)(p13;q22) translocation, fusing the ETV6 andAML1 genes, is the most frequent chromosomal translocation associated with pediatric B-cell precursor acute lymphoblastic leukemia. Although the genomic organization of 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 the large, hitherto unknown size of AML1 intron 1. Here, we report the mapping of the AML1 gene between exons 1 and 3, cloning of ETV6-AML1 breakpoints from different patients, and localization of the AML1 breakpoints withinAML1 intron 1. In contrast to the tightly clustered ETV6breakpoints, the AML1 breakpoints were found to be dispersed throughout AML1 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 matches were present only on the ETV6 alleles and not on the AML1 alleles, making it unlikely that the translocations were mediated by a simple V(D)J recombination mistake. Interestingly, several breakpoints as well as a stable insertion polymorphism mapped close to a polymorphic, alternating purine-pyrimidine tract in the ETV6 gene, suggesting that this region may be prone to DNA recombination events such as insertions or translocations. Finally, the presence of an insertional polymorphism within the ETV6 bcr must be recognized to avoid incorrect genotype designation based on Southern blot analysis.

The Origin and Nature of Tightly Clustered BTG1 Deletions in Precursor B-Cell Acute Lymphoblastic Leukemia Support a Model of Multiclonal Evolution

“…Illegitimate recombination events at cryptic RSS motifs have been implicated in several recurrent chromosomal abnormalities in lymphoid malignancies, such as translocations and deletions. For example, both ETV6-RUNX1 and BCR-ABL1 translocations have been suggested to arise from mistargeting of RAG proteins that facilitate RAG-mediated transposition or at least create one of the initiating lesions in the form of nicks [29] – [31] . This mistargeting of RAG proteins may occur as a rare spontaneous event during lymphocyte differentiation, but may also result from increased or prolonged RAG activity in leukemic lymphoid blasts.…”

Genomic anatomy of the specific reciprocal translocation t(15;17) in acute promyelocytic leukemia

“…Other models have suggested that some genomic regions may be particularly susceptible to breakage (Wiemels et al, 2000). For example, a breakpoint microcluster within TEL was found close to a highly repetitive purine/pyrimidine repeat region that was prone to denature under physiological conditions (Thandla et al, 1999;Wiemels and Greaves, 1999). Similarly, scaffold attachment regions are associated with a subset of MLL translocation breakpoints (Broeker et al, 1996) and are believed to contain regions that become single-stranded under stress (Benham et al, 1997).…”

Characterization of a newly identified ETV6-NTRK3 fusion transcript in acute myeloid leukemia

“…ETV6 is located on band 12p13 which is genetically unstable and thus susceptible to chromosomal rearrangements [ 6 ]. In recent years ETV6 was shown to be involved in a variety of translocations associated with hematological malignancies of both myeloid as well as lymphoid origin [ 1 , 7 ]. The diversity of ETV6 rearrangements is striking considering that the breakpoints do not cluster within a particular region of the gene [ 4 ].…”