Translocation junctions in TCF3-PBX1 acute lymphoblastic leukemia/lymphoma cluster near transposable elements

Hematolymphoid neoplasms frequently harbor recurrent genetic abnormalities. Some of the most well recognized lesions are chromosomal translocations, and many of these are known to play pivotal roles in pathogenesis. In lymphoid malignancies, some translocations result from erroneous V(D)J-type events. However, other translocation junctions appear randomly positioned and their underlying mechanisms are not understood.

We tested the hypothesis that genomic repeats, including both simple tandem and interspersed repeats, are involved in chromosomal translocations arising in hematopoietic malignancies. Using a database of translocation junctions and RepeatMasker annotations of the reference genome assembly, we measured the proximity of translocation sites to their nearest repeat. We examined 1,174 translocation breakpoints from 10 classifications of hematolymphoid neoplasms. We measured significance using Student's t-test, and we determined a false discovery rate using a random permutation statistics technique.

Most translocations showed no propensity to involve genomic repeats. However, translocation junctions at the transcription factor 3 (TCF3)/E2A immunoglobulin enhancer binding factors E12/E47 (E2A) locus clustered within, or in proximity to, transposable element sequences. Nearly half of reported TCF3 translocations involve a MER20 DNA transposon. Based on this observation, we propose this sequence is important for the oncogenesis of TCF3-PBX1 acute lymphoblastic leukemia.