Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 134K) PPT slides of all figures Supplemental Material Index Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Marculescu, R. Articles by Nadel, B. Search for Related Content PubMed PubMed Citation Articles by Marculescu, R. Articles by Nadel, B. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Lymphoma Social Bookmarking                            What's this?

Original Article

: A Functional Assessment of Genomic Instability by Cryptic Sites

Rodrig Marculescu¹, Trang Le¹, Paul Simon², Ulrich Jaeger¹ and Bertrand Nadel¹

¹ Department of Internal Medicine I, Division of Hematology
² Department of Surgery, University of Vienna, A-1090 Vienna, Austria

Address correspondence to Bertrand Nadel, Department of Internal Medicine I, Division of Hematology, University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Phone: 43-1-40400-4999; Fax: 43-1-40400-7842; E-mail: Bertrand.Nadel{at}akh-wien.ac.at

Most lymphoid malignancies are initiated by specific chromosomal translocations between immunoglobulin (Ig)/T cell receptor (TCR) gene segments and cellular proto-oncogenes. In many cases, illegitimate V(D)J recombination has been proposed to be involved in the translocation process, but this has never been functionally established. Using extra-chromosomal recombination assays, we determined the ability of several proto-oncogenes to target V(D)J recombination, and assessed the impact of their recombinogenic potential on translocation rates in vivo. Our data support the involvement of 2 distinct mechanisms: translocations involving LMO2, TAL2, and TAL1 in T cell acute lymphoblastic leukemia (T-ALL), are compatible with illegitimate V(D)J recombination between a TCR locus and a proto-oncogene locus bearing a fortuitous but functional recombination site (type 1); in contrast, translocations involving BCL1 and BCL2 in B cell non-Hodgkin's lymphomas (B-NHL), are compatible with a process in which only the IgH locus breaks are mediated by V(D)J recombination (type 2). Most importantly, we show that the t(11;14)(p13;q32) translocation involving LMO2 is present at strikingly high frequency in normal human thymus, and that the recombinogenic potential conferred by the LMO2 cryptic site is directly predictive of the in vivo level of translocation at that locus. These findings provide new insights into the regulation forces acting upon genomic instability in B and T cell tumorigenesis.

Key Words: LMO2 • TAL2 • TAL1 • BCL2 mbr • BCL1 mtc

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

• Lange, M. D., Waldbieser, G. C., Lobb, C. J. (2009). Patterns of Receptor Revision in the Immunoglobulin Heavy Chains of a Teleost Fish. J. Immunol. 182: 5605-5622 [Abstract] [Full Text]  
• Lieber, M. R., Raghavan, S. C., Yu, K. (2008). Mechanistic Aspects of Lymphoid Chromosomal Translocations. J Natl Cancer Inst Monogr 2008: 8-11 [Abstract] [Full Text]  
• Zhang, M., Swanson, P. C. (2008). V(D)J Recombinase Binding and Cleavage of Cryptic Recombination Signal Sequences Identified from Lymphoid Malignancies. J. Biol. Chem. 283: 6717-6727 [Abstract] [Full Text]  
• Dik, W. A., Nadel, B., Przybylski, G. K., Asnafi, V., Grabarczyk, P., Navarro, J. M., Verhaaf, B., Schmidt, C. A., Macintyre, E. A., van Dongen, J. J. M., Langerak, A. W. (2007). Different chromosomal breakpoints impact the level of LMO2 expression in T-ALL. Blood 110: 388-392 [Abstract] [Full Text]  
• Raghavan, S. C., Swanson, P. C., Ma, Y., Lieber, M. R. (2005). Double-Strand Break Formation by the RAG Complex at the Bcl-2 Major Breakpoint Region and at Other Non-B DNA Structures In Vitro. Mol. Cell. Biol. 25: 5904-5919 [Abstract] [Full Text]  
• Soulier, J., Clappier, E., Cayuela, J.-M., Regnault, A., Garcia-Peydro, M., Dombret, H., Baruchel, A., Toribio, M.-L., Sigaux, F. (2005). HOXA genes are included in genetic and biologic networks defining human acute T-cell leukemia (T-ALL). Blood 106: 274-286 [Abstract] [Full Text]  
• Raghavan, S. C., Chastain, P., Lee, J. S., Hegde, B. G., Houston, S., Langen, R., Hsieh, C.-L., Haworth, I. S., Lieber, M. R. (2005). Evidence for a Triplex DNA Conformation at the bcl-2 Major Breakpoint Region of the t(14;18) Translocation. J. Biol. Chem. 280: 22749-22760 [Abstract] [Full Text]  
• Tsuji, H., Ishii-Ohba, H., Katsube, T., Ukai, H., Aizawa, S., Doi, M., Hioki, K., Ogiu, T. (2004). Involvement of Illegitimate V(D)J Recombination or Microhomology-Mediated Nonhomologous End-Joining in the Formation of Intragenic Deletions of the Notch1 Gene in Mouse Thymic Lymphomas. Cancer Res. 64: 8882-8890 [Abstract] [Full Text]  
• Raghavan, S. C., Houston, S., Hegde, B. G., Langen, R., Haworth, I. S., Lieber, M. R. (2004). Stability and Strand Asymmetry in the Non-B DNA Structure at the bcl-2 Major Breakpoint Region. J. Biol. Chem. 279: 46213-46225 [Abstract] [Full Text]  
• Langerak, A. W., Nadel, B., de Torbal, A., Wolvers-Tettero, I. L. M., van Gastel-Mol, E. J., Verhaaf, B., Jager, U., van Dongen, J. J. M. (2004). Unraveling the Consecutive Recombination Events in the Human IGK Locus. J. Immunol. 173: 3878-3888 [Abstract] [Full Text]  
• Boehden, G. S., Restle, A., Marschalek, R., Stocking, C., Wiesmuller, L. (2004). Recombination at chromosomal sequences involved in leukaemogenic rearrangements is differentially regulated by p53. Carcinogenesis 25: 1305-1313 [Abstract] [Full Text]  
• Hirt, C., Schuler, F., Dolken, L., Schmidt, C. A., Dolken, G. (2004). Low prevalence of circulating t(11;14)(q13;q32)-positive cells in the peripheral blood of healthy individuals as detected by real-time quantitative PCR. Blood 104: 904-905 [Full Text]  
• Cowell, L. G., Davila, M., Yang, K., Kepler, T. B., Kelsoe, G. (2003). Prospective Estimation of Recombination Signal Efficiency and Identification of Functional Cryptic Signals in the Genome by Statistical Modeling. JEM 197: 207-220 [Abstract] [Full Text]  
• Kitagawa, Y., Inoue, K., Sasaki, S., Hayashi, Y., Matsuo, Y., Lieber, M. R., Mizoguchi, H., Yokota, J., Kohno, T. (2002). Prevalent Involvement of Illegitimate V(D)J Recombination in Chromosome 9p21 Deletions in Lymphoid Leukemia. J. Biol. Chem. 277: 46289-46297 [Abstract] [Full Text]  
• Wiemels, J. L., Leonard, B. C., Wang, Y., Segal, M. R., Hunger, S. P., Smith, M. T., Crouse, V., Ma, X., Buffler, P. A., Pine, S. R. (2002). Site-specific translocation and evidence of postnatal origin of the t(1;19) E2A-PBX1 fusion in childhood acute lymphoblastic leukemia. Proc. Natl. Acad. Sci. USA 99: 15101-15106 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS