V(D)J-mediated translocations in lymphoid neoplasms: a functional assessment of genomic instability by cryptic sites.
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.
Marculescu
Rodrig
R
Department of Internal Medicine I, Division of Hematology, University of Vienna, A-1090 Vienna, Austria.
Le
Trang
T
Simon
Paul
P
Jaeger
Ulrich
U
Nadel
Bertrand
B
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002648:Child; D019938:Cyclin D1 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D006801:Humans; D060588:LIM Domain Proteins; D007945:Leukemia, Lymphoid / Q000235:genetics*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics; D008223:Lymphoma / Q000235:genetics*; D008667:Metalloproteins / Q000235:genetics; D051379:Mice; D008957:Models, Genetic; D009363:Neoplasm Proteins / Q000235:genetics; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D011995:Recombination, Genetic / Q000235:genetics*; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D013950:Thymus Gland / Q000166:cytology; D014157:Transcription Factors; D014178:Translocation, Genetic / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D019938:Cyclin D1; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; D008667:Metalloproteins; D009363:Neoplasm Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; C085117:LMO2 protein, human; C513188:Lmo2 protein, mouse; C000715470:MAS1 protein, human; C086540:TAL2 protein, human; C489366:Tal1 protein, mouse; C490129:Tal2 protein, mouse; C067143:TAL1 protein, human