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EMP1, a novel poor prognostic factor in pediatric leukemia regulates prednisolone resistance, cell proliferation,

I M Ariës1, I S Jerchel1, R E S R van den Dungen1

  • 1Department of Pediatric Oncology/Hematology, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.

Leukemia
|March 15, 2014
PubMed

Insights

Epithelial membrane protein 1 (EMP1) is overexpressed in pediatric acute lymphoblastic leukemia (ALL) resistant to prednisolone. Silencing EMP1 induces apoptosis, sensitizes cells to prednisolone, and predicts poor outcomes in B-cell ALL (BCP-ALL).

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Pediatric acute lymphoblastic leukemia (ALL) has a significant relapse rate (20%) often linked to prednisolone resistance.
  • Identifying novel therapeutic targets is crucial for overcoming treatment failure in ALL.

Purpose of the Study:

  • To identify novel druggable targets that can overcome prednisolone resistance in pediatric ALL.
  • To investigate the role of epithelial membrane protein 1 (EMP1) in prednisolone resistance and patient outcomes.

Main Methods:

  • Microarray gene expression profiling of 256 pediatric ALL patient samples.
  • EMP1 silencing using short hairpin RNA (shRNA) in ALL cell lines (BCP-ALL and T-ALL).
  • Assessment of apoptosis, cell-cycle arrest, prednisolone sensitivity, cell migration, and adhesion to mesenchymal stromal cells (MSCs).
  • Analysis of EMP1 expression in relation to patient survival and outcome via multivariate analysis.

Main Results:

  • EMP1 expression was significantly increased (3.4-fold) in vitro prednisolone-resistant ALL cells compared to sensitive cells.
  • EMP1 silencing induced apoptosis and cell-cycle arrest, reducing survival by 84.1% and sensitizing cells to prednisolone by up to 18.8-fold.
  • EMP1 silencing abrogated migration (78.3%) and adhesion (29.3%) to MSCs, indicating EMP1 mediates MSC-driven resistance.
  • High EMP1 expression in BCP-ALL patients correlated with poorer 5-year event-free survival (77% vs. 89%) and was identified as an independent predictor of poor outcome (HR: 2.36).

Conclusions:

  • EMP1 plays a significant role in prednisolone resistance in pediatric ALL, partly through mediating MSC interactions.
  • EMP1 signaling involves the Src kinase family.
  • EMP1 is a promising therapeutic target for developing new treatments to improve outcomes for pediatric BCP-ALL patients.

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