title: ERG transcriptional networks in primary acute leukemia cells implicate a role for ERG in deregulated kinase signaling.
abstract: High expression of the E26 transforming sequence related gene (ERG) is associated with poor prognosis in a subgroup of leukemia patients with acute myeloid (AML) and acute T-lymphoblastic leukemia (T-ALL). In a previous study we proposed that ERG overexpression may deregulate several signaling cascades in acute leukemia. Herein, we further expand those studies by identifying a consensus of biological targets in primary blasts of newly diagnosed acute leukemia patients. Our findings of chromatin immunoprecipitation-on-chip of primary samples revealed 48 significantly enriched single genes including DAAM1 and NUMB. Significantly enriched signaling pathways included WNT/β-catenin, p53, and PI3K/AKT with ERG overexpression inducing dephosphorylation of AKT(Ser473) relative to non ERG expressing K562 cells. Cell based ERG overexpression studies also revealed drug resistance to multi-kinase inhibitor, BAY 43-9006 (Sorafenib) and to the tyrosine kinase inhibitor TKI258. Thus in primary leukemic cells, ERG may contribute to the dysregulation of kinase signaling, which results in resistance to kinase inhibitors.
authors.affiliation: Department of Hematology and Oncology, Charité, University Hospital Berlin, Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Bock
authors.forename: Liliana H
authors.initials: LH
authors.lastname: Mochmann
authors.forename: Cornelia
authors.initials: C
authors.lastname: Schlee
authors.forename: Nasrin
authors.initials: N
authors.lastname: Farhadi-Sartangi
authors.forename: Stefanie
authors.initials: S
authors.lastname: Göllner
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
authors.forename: Claudia D
authors.initials: CD
authors.lastname: Baldus
mesh_terms: D019295:Computational Biology; D005434:Flow Cytometry; D005456:Fluorescent Dyes; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D018922:HL-60 Cells; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D000071230:Transcriptional Regulator ERG
chemical_list: C072312:ERG protein, human; D005456:Fluorescent Dyes; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG