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 M. 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

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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.

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

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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
T-cells
Aneuploidy
Oncogenes
M Phase Cell Cycle Checkpoints
Sequence Deletion
T-Lymphocytes
B-Cell Leukemia
T-Cell Leukemia
Homeodomain Proteins
Tumors
Neoplasms
B-Cell Lymphoma
Thymocytes
Transcription Factors
Down-Regulation
Genes
Chemical activation
Cells
Defects

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

De Keersmaecker, K., Real, P. J., Gatta, G. D., Palomero, T., Sulis, M. L., Tosello, V., ... 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

The TLX1 oncogene drives aneuploidy in T cell transformation. / De Keersmaecker, Kim; Real, Pedro J.; Gatta, Giusy Della; Palomero, Teresa; Sulis, Maria Luisa; 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 M.; 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.

In: Nature Medicine, Vol. 16, No. 11, 11.2010, p. 1321-1327.

Research output: Contribution to journalArticle

De Keersmaecker, K, Real, PJ, Gatta, GD, 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, EM, Racevskis, J, Wiernik, PH, Rowe, JM, Soulier, J, Avran, D, Cavé, H, Dastugue, N, Raimondi, S, Meijerink, JPP, Cordon-Cardo, C, Califano, A & Ferrando, AA 2010, 'The TLX1 oncogene drives aneuploidy in T cell transformation', Nature Medicine, vol. 16, no. 11, pp. 1321-1327. https://doi.org/10.1038/nm.2246
De Keersmaecker K, Real PJ, Gatta GD, Palomero T, Sulis ML, Tosello V et al. The TLX1 oncogene drives aneuploidy in T cell transformation. Nature Medicine. 2010 Nov;16(11):1321-1327. https://doi.org/10.1038/nm.2246
De Keersmaecker, Kim ; Real, Pedro J. ; Gatta, Giusy Della ; Palomero, Teresa ; Sulis, Maria Luisa ; 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 M. ; 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. / The TLX1 oncogene drives aneuploidy in T cell transformation. In: Nature Medicine. 2010 ; Vol. 16, No. 11. pp. 1321-1327.
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