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.
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors.forename: Giusy
authors.initials: G
authors.lastname: Della Gatta
authors.forename: Teresa
authors.initials: T
authors.lastname: Palomero
authors.forename: Arianne
authors.initials: A
authors.lastname: Perez-Garcia
authors.forename: Alberto
authors.initials: A
authors.lastname: Ambesi-Impiombato
authors.forename: Mukesh
authors.initials: M
authors.lastname: Bansal
authors.forename: Zachary W
authors.initials: ZW
authors.lastname: Carpenter
authors.forename: Kim
authors.initials: K
authors.lastname: De Keersmaecker
authors.forename: Xavier
authors.initials: X
authors.lastname: Sole
authors.forename: Luyao
authors.initials: L
authors.lastname: Xu
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Paietta
authors.forename: Janis
authors.initials: J
authors.lastname: Racevskis
authors.forename: Peter H
authors.initials: PH
authors.lastname: Wiernik
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Rowe
authors.forename: Jules P
authors.initials: JP
authors.lastname: Meijerink
authors.forename: Andrea
authors.initials: A
authors.lastname: Califano
authors.forename: Adolfo A
authors.initials: AA
authors.lastname: Ferrando
mesh_terms: D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism*; D053263:Gene Regulatory Networks / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes / Q000235:genetics; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D018398:Homeodomain Proteins; D011518:Proto-Oncogene Proteins; C493728:RUNX1 protein, human; C489494:TLX3 protein, human; D025521:Tumor Suppressor Proteins; C071250:TLX1 protein, human