@article{bb3fb5b0777949a3970a7ef30bae21c7,
title = "Reverse engineering of TLX oncogenic transcriptional networks identifies RUNX1 as tumor suppressor in T-ALL",
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.",
author = "{Della Gatta}, Giusy and Teresa Palomero and Arianne Perez-Garcia and Alberto Ambesi-Impiombato and Mukesh Bansal and Carpenter, {Zachary W.} and {De Keersmaecker}, Kim and Xavier Sole and Luyao Xu and Elisabeth Paietta and Janis Racevskis and Wiernik, {Peter H.} and Rowe, {Jacob M.} and Meijerink, {Jules P.} and Andrea Califano and Ferrando, {Adolfo A.}",
note = "Funding Information: This work was supported by the US National Institutes of Health (grants R01CA120196 and R01CA129382 to A.A.F.; and U24 CA114737 to E.P.), the New York Community Trust (A.A.F.), the Innovative Research Award by the Stand Up to Cancer Foundation (A.A.F.), the Eastern Cooperative Oncology Group tumor bank, the Leukemia and Lymphoma Society Scholar Award (A.A.F.), the Stichting Kinderen Kankervrij (KiKa; grant 2007-012) (J.P.M.) and the Dutch Cancer Society (KWF-EMCR 2006-3500) (J.P.M.). A.P.-G. is a postdoctoral researcher funded by the Rally Foundation. G.D.G. was supported by a Marie Curie International Outgoing fellowship. We thank S. Nimer (Memorial Sloan Kettering Cancer Center) for the pCDNA3 RUNX1 expression vector, D. Zhang (University of California, San Diego) for the pM-CSF-R-luc promoter reporter and the pCMV CBFB plasmids and J. Downing (St. Jude Children{\textquoteright}s Research Hospital) for the Runx1 knockout mice.",
year = "2012",
month = mar,
doi = "10.1038/nm.2610",
language = "English (US)",
volume = "18",
pages = "436--440",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "3",
}
