Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Oct 17;4(1):22.
doi: 10.1186/1759-8753-4-22.

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

Nemanja Rodić  1 , John G Zampella, Toby C Cornish, Sarah J Wheelan, Kathleen H Burns
Affiliations

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

Nemanja Rodić et al. Mob DNA. .

Abstract

Background: 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.

Results: 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.

Conclusions: 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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Experimental outline depicting a hypothetical translocation region encompassing three translocation junctions. An illustration on the left represents the hypothesis, where there is a spatial association (symbol X) between the three observed translocation junctions (red triangles) and the nearest repeated sequence (blue arrow). Similarly, an illustration on the right represents the null hypothesis, where there is no spatial association (symbol X’) between three randomly generated translocation junctions (broken triangles) and their nearest repeat (blue arrow). We compared actual translocation junctions to 1,000 randomly generated positions to identify translocation junction regions that consistently happen near repeats.
Figure 2
Figure 2
Translocation junctions in TCF3 occur at or near repeats. The Y-axis denotes the expected versus observed ratio of distances between translocation junctions and their nearest repeats. The X-axis denotes translocation loci analyzed. Other translocations examined were independent of local repeat content; expected versus observed ratios for these loci approach one (1). See Table 1 for abbreviations.
Figure 3
Figure 3
Schematic representation of a TCF3 locus including translocations and transposable elements. The red triangles represent individual translocation junctions, the blue arrows indicate transposable elements within TCF3, and the black rectangles identify TCF3 exons. Inset, TCF3 translocation junction density map within the MER20 transposon. Genome coordinates correspond to March 2006, NCBI36/hg18 human genome assembly. TCF3: Transcription factor 3; MER20: Medium reiteration frequency repetitive 20; L1: LINE-1 Long INterspersed Element 1; L2: Long INterspersed Element 2; Alu: Alu SINE; U6: Small nuclear RNA.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Lin C, Yang L, Tanasa B, Hutt K, Ju BG, Ohgi K, Zhang J, Rose DW, Fu XD, Glass CK, Rosenfeld MG. Nuclear receptor-induced chromosomal proximity and DNA breaks underlie specific translocations in cancer. Cell. 2009;4(6):1069–1083. doi: 10.1016/j.cell.2009.11.030. - DOI - PMC - PubMed
    1. Elliott B, Richardson C, Jasin M. Chromosomal translocation mechanisms at intronic alu elements in mammalian cells. Molecular cell. 2005;4(6):885–894. doi: 10.1016/j.molcel.2005.02.028. - DOI - PubMed
    1. Aplan PD, Chervinsky DS, Stanulla M, Burhans WC. Site-specific DNA cleavage within the MLL breakpoint cluster region induced by topoisomerase II inhibitors. Blood. 1996;4(7):2649–2658. - PubMed
    1. Libura J, Ward M, Solecka J, Richardson C. Etoposide-initiated MLL rearrangements detected at high frequency in human primitive hematopoietic stem cells with in vitro and in vivo long-term repopulating potential. Eur J Haematol. 2008;4(3):185–195. doi: 10.1111/j.1600-0609.2008.01103.x. - DOI - PMC - PubMed
    1. Lee E, Iskow R, Yang L, Gokcumen O, Haseley P, Luquette LJ 3rd, Lohr JG, Harris CC, Ding L, Wilson RK, Wheeler DA, Gibbs RA, Kucherlapati R, Lee C, Kharchenko PV, Park PJ. Cancer Genome Atlas Research Network. Landscape of somatic retrotransposition in human cancers. Science. 2012;4(6097):967–971. doi: 10.1126/science.1222077. - DOI - PMC - PubMed

LinkOut - more resources