Recombinase, chromosomal translocations and lymphoid neoplasia: targeting mistakes and repair failures.
A large number of lymphoid malignancies is characterized by specific chromosomal translocations, which are closely linked to the initial steps of pathogenesis. The hallmark of these translocations is the ectopic activation of a silent proto-oncogene through its relocation at the vicinity of an active regulatory element. Due to the unique feature of lymphoid cells to somatically rearrange and mutate receptor genes, and to the corresponding strong activity of the immune enhancers/promoters at that stage of cell development, B- and T-cell differentiation pathways represent propitious targets for chromosomal translocations and oncogene activation. Recent progress in the understanding of the V(D)J recombination process has allowed a more accurate definition of the translocation mechanisms involved, and has revealed that V(D)J-mediated translocations result both from targeting mistakes of the recombinase, and from illegitimate repair of the V(D)J recombination intermediates. Surprisingly, V(D)J-mediated translocations turn out to be restricted to two specific sub-types of lymphoid malignancies, T-cell acute lymphoblastic leukemias, and a restricted set of mature B-cell Non-Hodgkin's lymphomas.
Marculescu
Rodrig
R
Department of Internal Medicine I, Division of Hematology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
Vanura
Katrina
K
Montpellier
Bertrand
B
Roulland
Sandrine
S
Le
Trang
T
Navarro
Jean-Marc
JM
Jäger
Ulrich
U
McBlane
Fraser
F
Nadel
Bertrand
B
D001402:B-Lymphocytes / Q000737:chemistry; D004260:DNA Repair; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics*; D016393:Lymphoma, B-Cell / Q000235:genetics*; D008957:Models, Genetic; D000090063:Proto-Oncogene Mas; D045522:Recombinases / Q000235:genetics*; D011995:Recombination, Genetic; D013601:T-Lymphocytes / Q000737:chemistry; D014178:Translocation, Genetic
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D045522:Recombinases