Reverse Engineering of TLX Oncogenic Transcriptional Networks Identifies RUNX1 As Tumor Suppressor in T-ALL

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2012 Feb 28

PMID 22366949

Citations 90

Authors

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

Affiliations

Soon will be listed here.

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.

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