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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
The TLX1 oncogene drives aneuploidy in T cell transformation
Nature Medicine. 2010 Nov;16(11) :1321-1327
PMCID: PMC2974790   
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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.
Notes
De Keersmaecker, Kim Real, Pedro J. Della Gatta, Giusy Palomero, Teresa Luisa Sulis, Maria Tosello, Valeria Van Vlierberghe, Pieter Barnes, Kelly Castillo, Mireia Sole, 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 Cave, Helene Dastugue, Nicole Raimondi, Susana Meijerink, Jules P. P. Cordon-Cardo, Carlos Califano, Andrea Ferrando, Adolfo A. Nature publishing group New york 675tv