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Title: The TLX1 oncogene drives aneuploidy in T-cell transformation
Author: Keersmaecker, Kim De
Real, Pedro Jose
Gatta, Giusy Della
Palomero, Teresa
Sulis, Maria Luisa
Tosello, Valeria
Van Vlierberghe, Pieter
Barnes, Kelly
Castillo, Mireia
Solé Acha, Xavier
Hadler, Michael
Lenz, Jack
Aplan, Peter D.
Kelliher, Michelle
Kee, Barbara L.
Pandolfi, Pier Paolo
Kappes, Dietmar
Gounari, Fotini
Petrie, Howard
Van der Meulen, Joni
Speleman, Frank
Paietta, Elisabeth
Racevskis, Janis
Wiernik, Peter H.
Rowe, Jacob M.
Soulier, Jean
Avran, David
Cavé, Hélène
Dastugue, Nicole
Raimondi, Susana
Meijerink, Jules P. P.
Cordon Cardo, Carlos
Califano, Andrea
Ferrando, Adolfo A.
Keywords: Leucèmia limfocítica crònica
Chronic lymphocytic leukemia
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, num. 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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