ERG induces a mesenchymal-like state associated with chemoresistance in leukemia cells
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Liliana H. Mochmann1, Martin Neumann1, Eva K. von der Heide1, Verena Nowak2, Anja A. Kühl3, Jutta Ortiz-Tanchez1, Juliane Bock1, Wolf K. Hofmann2, Claudia D. Baldus1
1 Department of Hematology and Oncology, Charité University Medicine Berlin, Berlin, Germany
2 Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany
3 Department of Gastroenterology, Infectiology and Rheumatology, Charité University Medicine Berlin, Berlin, Germany
Claudia D. Baldus, email:
Keywords: ERG, ERK, EMT, Chemoresistance
Received: September 26, 2013 Accepted: December 3, 2013 Published: December 4, 2013
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.
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