Different chromosomal breakpoints impact the level of LMO2 expression in T-ALL.
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.
Dik
Willem A
WA
Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands.
Nadel
Bertrand
B
Przybylski
Grzegorz K
GK
Asnafi
Vahid
V
Grabarczyk
Piotr
P
Navarro
Jean Marc
JM
Verhaaf
Brenda
B
Schmidt
Christian A
CA
Macintyre
Elizabeth A
EA
van Dongen
Jacques J M
JJ
Langerak
Anton W
AW
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
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; C085117:LMO2 protein, human; D008667:Metalloproteins; D011518:Proto-Oncogene Proteins