Cargando…
ERG induces a mesenchymal-like state associated with chemoresistance in leukemia cells
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 repor...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2013
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964212/ https://www.ncbi.nlm.nih.gov/pubmed/24504051 |
_version_ | 1782308604875898880 |
---|---|
author | Mochmann, Liliana H. Neumann, Martin von der Heide, Eva K. Nowak, Verena Kühl, Anja A. Ortiz-Tanchez, Jutta Bock, Juliane Hofmann, Wolf K. Baldus, Claudia D. |
author_facet | Mochmann, Liliana H. Neumann, Martin von der Heide, Eva K. Nowak, Verena Kühl, Anja A. Ortiz-Tanchez, Jutta Bock, Juliane Hofmann, Wolf K. Baldus, Claudia D. |
author_sort | Mochmann, Liliana H. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3964212 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-39642122014-03-25 ERG induces a mesenchymal-like state associated with chemoresistance in leukemia cells Mochmann, Liliana H. Neumann, Martin von der Heide, Eva K. Nowak, Verena Kühl, Anja A. Ortiz-Tanchez, Jutta Bock, Juliane Hofmann, Wolf K. Baldus, Claudia D. Oncotarget Research Paper 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. Impact Journals LLC 2013-12-04 /pmc/articles/PMC3964212/ /pubmed/24504051 Text en Copyright: © 2014 Mochmann et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Mochmann, Liliana H. Neumann, Martin von der Heide, Eva K. Nowak, Verena Kühl, Anja A. Ortiz-Tanchez, Jutta Bock, Juliane Hofmann, Wolf K. Baldus, Claudia D. ERG induces a mesenchymal-like state associated with chemoresistance in leukemia cells |
title | ERG induces a mesenchymal-like state associated with chemoresistance in leukemia cells |
title_full | ERG induces a mesenchymal-like state associated with chemoresistance in leukemia cells |
title_fullStr | ERG induces a mesenchymal-like state associated with chemoresistance in leukemia cells |
title_full_unstemmed | ERG induces a mesenchymal-like state associated with chemoresistance in leukemia cells |
title_short | ERG induces a mesenchymal-like state associated with chemoresistance in leukemia cells |
title_sort | erg induces a mesenchymal-like state associated with chemoresistance in leukemia cells |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964212/ https://www.ncbi.nlm.nih.gov/pubmed/24504051 |
work_keys_str_mv | AT mochmannlilianah erginducesamesenchymallikestateassociatedwithchemoresistanceinleukemiacells AT neumannmartin erginducesamesenchymallikestateassociatedwithchemoresistanceinleukemiacells AT vonderheideevak erginducesamesenchymallikestateassociatedwithchemoresistanceinleukemiacells AT nowakverena erginducesamesenchymallikestateassociatedwithchemoresistanceinleukemiacells AT kuhlanjaa erginducesamesenchymallikestateassociatedwithchemoresistanceinleukemiacells AT ortiztanchezjutta erginducesamesenchymallikestateassociatedwithchemoresistanceinleukemiacells AT bockjuliane erginducesamesenchymallikestateassociatedwithchemoresistanceinleukemiacells AT hofmannwolfk erginducesamesenchymallikestateassociatedwithchemoresistanceinleukemiacells AT baldusclaudiad erginducesamesenchymallikestateassociatedwithchemoresistanceinleukemiacells |