title: Different chromosomal breakpoints impact the level of LMO2 expression in T-ALL.
abstract: The t(11;14)(p13;q11) is presumed to arise from an erroneous T-cell receptor delta 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 9 new t(11;14)(p13;q11)-positive T-cell acute lymphoblastic leukemia (T-ALL) as well as normal thymocytes. Our data support the involvement of 2 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) translocations. 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.
authors.affiliation: Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Willem A
authors.initials: WA
authors.lastname: Dik
authors.forename: Bertrand
authors.initials: B
authors.lastname: Nadel
authors.forename: Grzegorz K
authors.initials: GK
authors.lastname: Przybylski
authors.forename: Vahid
authors.initials: V
authors.lastname: Asnafi
authors.forename: Piotr
authors.initials: P
authors.lastname: Grabarczyk
authors.forename: Jean Marc
authors.initials: JM
authors.lastname: Navarro
authors.forename: Brenda
authors.initials: B
authors.lastname: Verhaaf
authors.forename: Christian A
authors.initials: CA
authors.lastname: Schmidt
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Macintyre
authors.forename: Jacques J M
authors.initials: JJ
authors.lastname: van Dongen
authors.forename: Anton W
authors.initials: AW
authors.lastname: Langerak
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D019457:Chromosome Breakage; D002880:Chromosomes, Human, Pair 11; D002883:Chromosomes, Human, Pair 14; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics*; D019676:Genes, T-Cell Receptor delta; D006801:Humans; D060588:LIM Domain Proteins; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000209:etiology / Q000235:genetics*; D008667:Metalloproteins / Q000032:analysis / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D014178:Translocation, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; C085117:LMO2 protein, human; D008667:Metalloproteins; D011518:Proto-Oncogene Proteins