title: ERG induces a mesenchymal-like state associated with chemoresistance in leukemia cells.
abstract: Overexpression of the oncogene ERG (ETS-related gene) is an adverse prognostic factor in acute myeloid and T-cell lymphoblastic leukemia (AML and T-ALL). We hypothesize that ERG overexpression is associated with primary drug resistance thereby influencing the outcome in leukemia. We previously reported a cell-line based model of ERG overexpression which induced a potentially chemo-resistant spindle shape cell type. Herein, we report a specific transcriptional gene signature for the observed spindle shaped morphology. Genes significantly over-expressed after ERG induction strongly resembled adhesive mesenchymal-like genes that included integrins (ITGA10, ITGB5, ITGB3, ITGA2B), CD44, and CD24. Interestingly, the mesenchymal-like signature was accompanied by the repression of DNA chromatin remodeling and DNA repair genes, such as CHEK1, EZH2, SUZ12, and DNMT3a. The ERG-induced mesenchymal-like signature positively correlated with TMPRSS2-ERG prostate tissues and invasive breast cancer mRNA expression datasets reflecting a general ERG-driven pattern of malignancy. Furthermore, inhibitors modulating ERG druggable pathways WNT, PKC, and AKT, and chemotherapeutic agent cytarabine revealed ERG-induced drug resistance. In particular, PKC412 treatment enhanced proliferative rates and promoted spindle shape formation in ERG-induced cells. Nilotinib and dasatinib were effective at abolishing ERG-induced cells. Moreover, ERG overexpression also led to an increase in double strand breaks. This report provides mechanistic clues into ERG-driven drug resistance in the poor prognostic group of high ERG expressers, provides insight to improved drug targeted therapies, and provides novel markers for a mesenchymal-like state in acute leukemia.
authors: Department of Hematology and Oncology, Charité University Medicine Berlin, Berlin, Germany.
authors: Liliana H
authors: LH
authors: Mochmann
authors: Martin
authors: M
authors: Neumann
authors: Eva K
authors: EK
authors: von der Heide
authors: Verena
authors: V
authors: Nowak
authors: Anja A
authors: AA
authors: Kühl
authors: Jutta
authors: J
authors: Ortiz-Tanchez
authors: Juliane
authors: J
authors: Bock
authors: Wolf K
authors: WK
authors: Hofmann
authors: Claudia D
authors: CD
authors: Baldus
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D003561:Cytarabine / Q000494:pharmacology; D004260:DNA Repair; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D006801:Humans; D020014:K562 Cells; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011379:Prognosis; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000071230:Transcriptional Regulator ERG
chemical_list: D000964:Antimetabolites, Antineoplastic; C072312:ERG protein, human; D011743:Pyrimidines; D013844:Thiazoles; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D003561:Cytarabine; D011505:Protein-Tyrosine Kinases; C498826:nilotinib; D000069439:Dasatinib