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

Nature Medicine volume 18, pages 436–440 (2012)Cite this article

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Abstract

The TLX1 and TLX3 transcription factor oncogenes have a key role in the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL)1,2. 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.

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Figure 1: TLX1- and TLX3-expressing T-ALLs are associated with a distinct gene expression signature that is highly enriched in downregulated direct target genes of TLX1 and TLX3 as determined by ChIP-chip.
Figure 2: An ARACNe transcriptional network identifies TLX1 and TLX3 direct targets and genes differentially expressed in TLX1- and TLX3-expressing T-ALLs.
Figure 3: Reverse engineering and structure analysis of the TLXi.
Figure 4: RUNX1 mutations in T-ALL.

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Acknowledgements

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's Research Hospital) for the Runx1 knockout mice.

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Authors and Affiliations

  1. Institute for Cancer Genetics, Columbia University, New York, New York, USA

    Giusy Della Gatta, Teresa Palomero, Arianne Perez-Garcia, Alberto Ambesi-Impiombato, Zachary W Carpenter, Luyao Xu, Andrea Califano & Adolfo A Ferrando

  2. Department of Pathology, Columbia University Medical Center, New York, New York, USA

    Teresa Palomero & Adolfo A Ferrando

  3. Joint Centers for Systems Biology, Columbia University, New York, New York, USA

    Mukesh Bansal & Andrea Califano

  4. Department of Molecular and Developmental Genetics, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium

    Kim De Keersmaecker

  5. Center for Human Genetics, K.U. Leuven, Leuven, Belgium

    Kim De Keersmaecker

  6. Biomarkers and Susceptibility Unit, Catalan Institute of Oncology, Instituto de Investigación Biomédica de Bellvitge (IDIBELL), L'Hospitalet, Barcelona, Spain

    Xavier Sole

  7. Biomedical Research Centre Network for Epidemiology and Public Health, Catalan Institute of Oncology, IDIBELL, L'Hospitalet, Barcelona, Spain

    Xavier Sole

  8. Montefiore Medical Center North, New York, New York, USA

    Elisabeth Paietta, Janis Racevskis & Peter H Wiernik

  9. New York Medical College, New York, New York, USA

    Elisabeth Paietta, Janis Racevskis & Peter H Wiernik

  10. Rambam Medical Center and Technion, Israel Institute of Technology, Haifa, Israel

    Jacob M Rowe

  11. Department of Pediatric Oncology and Hematology, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands

    Jules P Meijerink

  12. Department of Pediatrics, Columbia University Medical Center, New York, New York, USA

    Adolfo A Ferrando

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  1. Giusy Della Gatta
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Contributions

G.D.G. performed expression and network analysis of human and mouse leukemias, identified RUNX1 mutations in T-ALL and wrote the manuscript; T.P. performed ChIP-chip analysis of TLX1 and TLX3 and the RNA interference experiments; A.P.-G. analyzed the tumor activity of RUNX1; A.A.-I. and M.B. performed network analysis; Z.W.C. performed structure modeling of RUNX1 mutant protein; K.D.K. performed mouse studies; X.S. analyzed ChIP-chip data; L.X. performed mouse studies; E.P., J.R., P.H.W. and J.M.R. provided clinical specimens and correlative data on adult T-ALL samples; J.P.M. contributed clinical specimens and performed microarray analysis; A.C. supervised research; and A.A.F. designed the study, supervised research and wrote the manuscript.

Corresponding author

Correspondence to Adolfo A Ferrando.

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The authors declare no competing financial interests.

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Supplementary Methods, Supplementary Figures 1–13 and Supplementary Tables 1–11 (PDF 5740 kb)

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Della Gatta, G., Palomero, T., Perez-Garcia, A. et al. Reverse engineering of TLX oncogenic transcriptional networks identifies RUNX1 as tumor suppressor in T-ALL. Nat Med 18, 436–440 (2012). https://doi.org/10.1038/nm.2610

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