Reverse engineering of TLX oncogenic transcriptional networks identifies RUNX1 as tumor suppressor in T-ALL

Giusy Della Gatta, Teresa Palomero, Arianne Perez-Garcia, Alberto Ambesi-Impiombato, Mukesh Bansal, Zachary W. Carpenter, Kim De Keersmaecker, Xavier Sole, Luyao Xu, Elisabeth Paietta, Janis Racevskis, Peter H. Wiernik, Jacob M. Rowe, Jules P. Meijerink, Andrea Califano, Adolfo A. Ferrando

Research output: Contribution to journalArticle

101 Scopus citations

Abstract

The TLX1 and TLX3 transcription factor oncogenes have a key role in the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL). Here we used reverse engineering of global transcriptional networks to decipher the oncogenic regulatory circuit controlled by TLX1 and TLX3. This systems biology analysis defined T cell leukemia homeobox 1 (TLX1) and TLX3 as master regulators of an oncogenic transcriptional circuit governing T-ALL. Notably, a network structure analysis of this hierarchical network identified RUNX1 as a key mediator of the T-ALL induced by TLX1 and TLX3 and predicted a tumor-suppressor role for RUNX1 in T cell transformation. Consistent with these results, we identified recurrent somatic loss-of-function mutations in RUNX1 in human T-ALL. Overall, these results place TLX1 and TLX3 at the top of an oncogenic transcriptional network controlling leukemia development, show the power of network analyses to identify key elements in the regulatory circuits governing human cancer and identify RUNX1 as a tumor-suppressor gene in T-ALL.

Original languageEnglish (US)
Pages (from-to)436-440
Number of pages5
JournalNature Medicine
Volume18
Issue number3
DOIs
StatePublished - Mar 1 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Della Gatta, G., Palomero, T., Perez-Garcia, A., Ambesi-Impiombato, A., Bansal, M., Carpenter, Z. W., De Keersmaecker, K., Sole, X., Xu, L., Paietta, E., Racevskis, J., Wiernik, P. H., Rowe, J. M., Meijerink, J. P., Califano, A., & Ferrando, A. A. (2012). Reverse engineering of TLX oncogenic transcriptional networks identifies RUNX1 as tumor suppressor in T-ALL. Nature Medicine, 18(3), 436-440. https://doi.org/10.1038/nm.2610