Department of Pediatric Oncology/Hematology, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
Clinic of Paediatric Haematology and Oncology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
Leukemia. 2014 Sep;28(9):1828-37. doi: 10.1038/leu.2014.80. Epub 2014 Feb 20.
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.
仍有 20%的儿科急性淋巴细胞白血病（ALL）患者在当前治疗策略后或之后复发。治疗失败与对泼尼松龙的耐药性有关。我们旨在寻找新的可调节泼尼松龙耐药性的药物靶点。我们生成了 256 名儿科 ALL 患者样本的微阵列基因表达谱，并发现体外泼尼松龙耐药患者中上皮膜蛋白 1（EMP1）的表达增加了 3.4 倍（P=0.003）。在 6 个前体-B 急性淋巴细胞白血病（BCP-ALL）和 T 急性淋巴细胞白血病细胞系中沉默 EMP1 诱导细胞凋亡和细胞周期停滞，导致与未沉默对照转导细胞（非沉默对照短发夹 RNA，shNSC）相比存活率降低 84.1±4.5%（P=0.014）。此外，EMP1 沉默使泼尼松龙敏感性增加了 18.8 倍（P<0.001）。EMP1 沉默还使细胞向间充质基质细胞（MSCs）的迁移和粘附减少了 78.3±9.0%和 29.3±4.1%，与 shNSC 相比（P<0.05）。我们发现 EMP1 有助于 MSC 介导的泼尼松龙耐药性。通路分析表明，EMP1 通过Src 激酶家族发出信号。EMP1 高表达的 BCP-ALL 患者的 5 年无事件生存率比 EMP1 低表达的患者差（77±2%对 89±2%，P=0.003）。考虑白细胞计数、年龄、泼尼松龙耐药性和亚型的多变量分析确定 EMP1 是 BCP-ALL 预后不良的独立预测因子（P=0.004，危险比：2.36（1.31-4.25）。这项研究提供了临床前证据，表明 EMP1 是开发药物的一个有趣候选物，以优化 BCP-ALL 的治疗。
