Abstract
Still 20% of pediatric acute lymphoblastic leukemia (ALL) patients relapse on or after current treatment strategies. Treatment failure is associated with resistance to prednisolone. We aimed to find new druggable targets that modulate prednisolone resistance. We generated microarray gene expression profiles of 256 pediatric ALL patient samples and identified a 3.4-fold increase in epithelial membrane protein 1 (EMP1) expression in in vitro prednisolone-resistant compared with -sensitive patients (P=0.003). EMP1 silencing in six precursor-B ALL (BCP-ALL) and T-ALL cell lines induced apoptosis and cell-cycle arrest leading to 84.1±4.5% reduction in survival compared with non-silencing control transduced cells (non-silencing control short hairpin, shNSC) (P=0.014). Moreover, EMP1 silencing sensitized to prednisolone up to 18.8-fold (P<0.001). EMP1 silencing also abrogated migration and adhesion to mesenchymal stromal cells (MSCs) by 78.3±9.0 and 29.3±4.1% compared with shNSC (P<0.05). We discovered that EMP1 contributes to MSC-mediated prednisolone resistance. Pathway analysis indicated that EMP1 signals through the Src kinase family. EMP1-high BCP-ALL patients showed a poorer 5-year event-free survival compared with EMP1-low patients (77±2 vs 89±2%, P=0.003). Multivariate analysis taking along white blood cell count, age, prednisolone resistance and subtype identified EMP1 as an independent predictor for poor outcome in BCP-ALL (P=0.004, hazard ratio: 2.36 (1.31–4.25). This study provides preclinical evidence that EMP1 is an interesting candidate for drug development to optimize treatment of BCP-ALL.
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Acknowledgements
Dr D Campana, St. Jude Childrens’ Research Hospital, Memphis, USA, is highly acknowledged for supplying of MSC-hTERT cell line. This work was supported by the Dutch Cancer Society (MLDB, RP, EMCR 2005-3313 and AMC 2008-4265). The funding source had no role in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Author contributions
IMA designed and performed experiments, analyzed and interpreted data, and wrote the paper; ISJ and ERD assisted in part of the experiments; LCJVDB performed and analyzed flowsort experiment; JMB assisted with the statistical analysis of microarray data; MH and GE provided COALL survival data; RP and MLDB designed research, interpreted data and revised the paper.
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Ariës, I., Jerchel, I., van den Dungen, R. et al. EMP1, a novel poor prognostic factor in pediatric leukemia regulates prednisolone resistance, cell proliferation, migration and adhesion. Leukemia 28, 1828–1837 (2014). https://doi.org/10.1038/leu.2014.80
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DOI: https://doi.org/10.1038/leu.2014.80
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