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Blood, 1 July 2007, Vol. 110, No. 1, pp. 388-392.
Prepublished online as a Blood First Edition Paper on March 14, 2007; DOI 10.1182/blood-2006-12-064816.
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Submitted December 21, 2006
Accepted March 10, 2007
Different chromosomal breakpoints impact level of LMO2 expression in T-ALL
Willem A Dik, Bertrand Nadel, Grzegorz K Przybylski, Vahid Asnafi, Piotr Grabarczyk, Jean Marc Navarro, Brenda Verhaaf, Christian A. Schmidt, Elizabeth A. Macintyre, Jacques J.M. van Dongen, and Anton W Langerak*
Department of Immunology, Erasmus MC, Rotterdam, Netherlands
Centre d'immunologie de Marseille Luminy (CIML) INSERM-CNRS, Universite de la Mediterranee, Marseille, France
Institute of Human Genetics, Plish Academy of Sciences, Poznan, Poland
Department of Hematology, Universite Paris-Descartes, Faculte de Medecine, Hopital Necker Enfants Malades, Paris, France
Klinik fur Innere Medizin C, Universitat Greifswald, Greifswald, Germany
* Corresponding author; email: a.langerak{at}erasmusmc.nl.
The t(11;14)(p14;q11) is presumed to arise from erroneous TCRD V(D)J recombination, and to result in LMO2 activation. However, the mechanisms underlying this translocation and the resulting LMO2 activation are poorly defined. We performed combined in vivo, ex vivo, and in silico analyses on nine new t(11;14)(p13;q11) positive T-ALL as well as normal thymocytes. Our data support the involvement of two distinct t(11;14)(p13;q11) V(D)J-related translocation mechanisms. We provide compelling evidence that removal of a negative regulatory element from the LMO2 locus, rather than juxtaposition to the TCRD-enhancer, is the main determinant for LMO2 activation in the majority of t(11;14)(p13;q11). Furthermore, the position of the LMO2 breakpoints in T-ALL in the light of the occurrence of TCRD-LMO2 translocations in normal thymocytes points to a critical role for the exact breakpoint location in determining LMO2 activation levels and the consequent pressure for T-ALL development.
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