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Title: The Tlx1 Oncogene Drives Aneuploidy In T Cell Transformation
Author: De Keersmaecker, K
Real, Pj
Della Gatta, G
Palomero, T
Sulis, Ml
Tosello, V
Van Vlierberghe, P
Barnes, K
Castillo, M
Sole, X
Hadler, M
Lenz, J
Aplan, Pd
Kelliher, M
Kee, Bl
Pandolfi, Pp
Kappes, D
Gounari, F
Petrie, H
Van Der Meulen, J
Speleman, F
Paietta, E
Racevskis, J
Wiernik, Ph
Rowe, Jm
Soulier, J
Avran, D
Cave, H
Dastugue, N
Raimondi, S
Meijerink, Jpp
Cordon-cardo, C
Califano, A
Ferrando, Aa
Issue Date: 24-Oct-2010
Publisher: Nature Publishing Group
Abstract: The TLX1 oncogene (encoding the transcription factor T cell leukemia homeobox protein-1) has a major role in the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL). However, the specific mechanisms of T cell transformation downstream of TLX1 remain to be elucidated. Here we show that transgenic expression of human TLX1 in mice induces T-ALL with frequent deletions and mutations in Bcl11b (encoding B cell leukemia/lymphoma-11B) and identify the presence of recurrent mutations and deletions in BCL11B in 16% of human T-ALLs. Most notably, mouse TLX1 tumors were typically aneuploid and showed a marked defect in the activation of the mitotic checkpoint. Mechanistically, TLX1 directly downregulates the expression of CHEK1 (encoding CHK1 checkpoint homolog) and additional mitotic control genes and induces loss of the mitotic checkpoint in nontransformed preleukemic thymocytes. These results identify a previously unrecognized mechanism contributing to chromosomal missegregation and aneuploidy active at the earliest stages of tumor development in the pathogenesis of cancer.
Note: Versió postprint del document publicat a:
It is part of: Nature Medicine, 2010, Vol. 16, Issue 11, P. 1321-1327
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Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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