The TLX1 oncogene drives aneuploidy in T cell transformation

Kim De Keersmaecker, Pedro J. Real, Giusy Della Gatta, Teresa Palomero, Maria Luisa Sulis, Valeria Tosello, Pieter Van Vlierberghe, Kelly Barnes, Mireia Castillo, Xavier Sole, Michael Hadler, Jack Lenz, Peter D. Aplan, Michelle Kelliher, Barbara L. Kee, Pier Paolo Pandolfi, Dietmar Kappes, Fotini Gounari, Howard Petrie, Joni Van Der MeulenFrank Speleman, Elisabeth Paietta, Janis Racevskis, Peter H. Wiernik, Jacob M. Rowe, Jean Soulier, David Avran, Hélène Cavé, Nicole Dastugue, Susana Raimondi, Jules P.P. Meijerink, Carlos Cordon-Cardo, Andrea Califano, Adolfo A. Ferrando

Research output: Contribution to journalArticle

106 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1321-1327
Number of pages7
JournalNature Medicine
Volume16
Issue number11
DOIs
StatePublished - Nov 2010

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    De Keersmaecker, K., Real, P. J., Gatta, G. D., Palomero, T., Sulis, M. L., Tosello, V., Van Vlierberghe, P., Barnes, K., Castillo, M., Sole, X., Hadler, M., Lenz, J., Aplan, P. D., Kelliher, M., Kee, B. L., Pandolfi, P. P., Kappes, D., Gounari, F., Petrie, H., ... Ferrando, A. A. (2010). The TLX1 oncogene drives aneuploidy in T cell transformation. Nature Medicine, 16(11), 1321-1327. https://doi.org/10.1038/nm.2246