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.
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Acknowledgements
This work was supported by a Blood Disease Research Project research grant from The New York Community Trust (A.A.F.); the US National Institutes of Health (grants R01CA120196 and R01CA129382 to A.A.F.; CA21765 to S.R. and U24 CA114737 to E.P.), the Spanish Ministry of Science and Innovation (fellowship EX-2006-0739 to P.J.R.), a Canceropole Ile-de-France Research research grant (J.S.), the Eastern Cooperative Oncology Group tumor bank and the European Organization for Research and Treatment of Cancer Children Leukemia Group, the Leukemia & Lymphoma Society Scholar Award (A.A.F.) and the Intramural Program of the US National Institutes of Health (P.D.A.). K.D.K. is a postdoctoral researcher funded by the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen and a recipient of a Belgian American Educational Foundation fellowship. D.A. is recipient of a predoctoral fellowship from the France National Cancer Institute. We are also grateful to T. Ludwig for helpful discussions, to J.C. Zúñiga-Pflücker (University of Toronto) for the OP9-DL1 cells, to F. Gounari (University of Chicago) for the pUC1017 vector and S. Cory (Walter and Eliza Hall Institute of Medical Research) and H.G. Wendel (Memorial Sloan Kettering Cancer Center) for the Vav-Bcl2 mouse line.
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K.D.K. performed cellular, genetic and molecular characterization of TLX1-induced tumors and preleukemic thymocytes, identified BCL11B mutations in mouse and human tumors and wrote the manuscript. P.J.R. generated the TLX1-transgenic mice and characterized the tumor phenotype. G.D.G. analyzed ChIP-on-chip data and gene expression signatures in human and mouse tumors. T.P. performed ChIP-on-chip. V.T. characterized mouse thymocytes. P.V.V. and K.D.K. analyzed aCGH data. M.L.S. performed mouse tumor microarray analysis. K.B. and M.H. analyzed TLX1-transgenic lines. M.C. performed histological and immunohistochemical studies. J.L., P.D.A., M.K., B.L.K., P.P.P., D.K. and F.G. provided mouse tumor samples. H.P. provided gene expression data on normal mouse thymocytes. X.S. analyzed ChIP-on-chip data. J.V.d.M. and F.S. analyzed BCL11B mutations in human T-ALL samples. S.R., H.C., N.D., J.S. and D.A. provided cytogenetic data on human T-ALLs. E.P., J.R., P.H.W. and J.M.R. provided human T-ALL specimens from Eastern Cooperative Oncology Group clinical trials. J.P.P.M. generated human expression profiling data and characterized human T-ALL samples. C.C.-C. supervised histological and immunohistochemical studies. A.C. supervised the bioinformatic data analysis. A.A.F. designed the study, supervised research and wrote the manuscript.
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De Keersmaecker, K., Real, P., Gatta, G. et al. The TLX1 oncogene drives aneuploidy in T cell transformation. Nat Med 16, 1321–1327 (2010). https://doi.org/10.1038/nm.2246
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DOI: https://doi.org/10.1038/nm.2246
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