Experimental and integrative analyses identify an ETS1 network downstream of BCR-ABL in chronic myeloid leukemia (CML)
| Autor: | Hind Rahban, Sarah Pagliaro, Emilie Cayssials, Christophe Desterke, Nathalie Sorel, Marie-Laure Bonnet, Jean-Claude Chomel, Maud Voldoire, Annelise Bennaceur-Griscelli, Ali G. Turhan |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Cancer Research Fusion Proteins bcr-abl Antineoplastic Agents Biology Transcriptome Cohort Studies Proto-Oncogene Protein c-ets-1 03 medical and health sciences Random Allocation hemic and lymphatic diseases Cell Line Tumor Leukemia Myelogenous Chronic BCR-ABL Positive Genetics medicine Humans RNA Messenger RNA Neoplasm Promoter Regions Genetic Molecular Biology Protein Kinase Inhibitors Epigenomics Aged Regulation of gene expression Aged 80 and over Oncogene Gene Expression Regulation Leukemic Gene Expression Profiling Myeloid leukemia Cell Biology Hematology medicine.disease Gene expression profiling Leukemia 030104 developmental biology Cancer research Disease Progression Imatinib Mesylate Female Blast Crisis Tyrosine kinase Signal Transduction |
| Zdroj: | Experimental hematology. 64 |
| ISSN: | 1873-2399 |
| Popis: | The BCR-ABL oncogene, the hallmark of chronic myeloid leukemia (CML), has been shown to activate several signaling pathways in leukemic cells. The natural history of this disease has been radically modified by tyrosine kinase inhibitors (TKIs). However, resistance to several lines of TKI therapies and progression to blast crisis (BC) remain significant concerns. To identify novel signaling pathways induced by BCR-ABL, we performed a transcriptome analysis in a BCR-ABL-expressing UT-7 cell line. More than 2000 genes differentially expressed between BCR-ABL-expressing and parental UT-7 cells were identified and ETS1 was found to be the most upregulated. ETS1 protein expression was also shown to be highly increased in UT-7 cells expressing BCR-ABL either constitutively or under the control of TET-inducible promoters. ETS1 expression is tyrosine-kinase dependent because it was reduced by TKIs. A significant increase of ETS1 messenger RNA (mRNA) expression was observed in blood cells from CML patients at diagnosis compared with healthy controls. Integration of publicly available chromatin immunoprecipitation sequencing and transcriptomic data with our results allowed us to identify potential ETS1 targets, some of which are involved in the progression of CML. The messenger RNA expression of two of these genes (DNM3 and LIMS1) was found to be associated with the absence of major cytogenetic response after 1 year of imatinib therapy. The present work demonstrates for the first time the involvement of the ETS1 transcriptional program in the experimental UT-7 model and a large cohort of CML patients. |
| Databáze: | OpenAIRE |
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