van der Sligte Naomi E, Kampen Kim R, ter Elst Arja, Scherpen Frank J G, Meeuwsen-de Boer Tiny G J, Guryev Victor, van Leeuwen Frank N, Kornblau Steven M, de Bont Eveline S J M
Division of Pediatric Oncology/Hematology, Department of Pediatrics, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
European Research Institute for The Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Oncotarget. 2015 Jun 20;6(17):14970-81. doi: 10.18632/oncotarget.3911.
Acute lymphoblastic leukemia (ALL) relapse remains a leading cause of cancer related death in children, therefore, new therapeutic options are needed. Recently, we showed that a peptide derived from Cyclic-AMP Responsive Element Binding Protein (CREB) was highly phosphorylated in pediatric leukemias. In this study, we determined CREB phosphorylation and mRNA levels showing that CREB expression was significantly higher in ALL compared to normal bone marrow (phosphorylation: P < 0.0001, mRNA: P = 0.004). High CREB and phospho-CREB expression was correlated with a lower median overall survival in a cohort of 140 adult ALL patients. ShRNA mediated knockdown of CREB in ALL cell lines blocked leukemic cell growth by inducing cell cycle arrest and apoptosis. Gene expression array analysis showed downregulation of CREB target genes regulating cell proliferation and glucose metabolism and upregulation of apoptosis inducing genes. Similar to CREB knockdown, the CREB inhibitor KG-501 decreased leukemic cell viability and induced apoptosis in ALL cell lines, as well as primary T-ALL samples, with cases showing high phospho-CREB levels being more sensitive than those with lower phospho-CREB levels. Together, these in vitro findings support an important role for CREB in the survival of ALL cells and identify this transcription factor as a potential target for treatment.
急性淋巴细胞白血病（ALL）复发仍然是儿童癌症相关死亡的主要原因，因此，需要新的治疗选择。最近，我们发现源自环磷酸腺苷反应元件结合蛋白（CREB）的一种肽在小儿白血病中高度磷酸化。在本研究中，我们测定了CREB的磷酸化和mRNA水平，结果显示ALL中CREB的表达显著高于正常骨髓（磷酸化：P < 0.0001，mRNA：P = 0.004）。在140例成人ALL患者队列中，高CREB和磷酸化CREB表达与较低的中位总生存期相关。在ALL细胞系中，shRNA介导的CREB敲低通过诱导细胞周期停滞和凋亡来阻断白血病细胞生长。基因表达阵列分析显示，调节细胞增殖和葡萄糖代谢的CREB靶基因下调，而凋亡诱导基因上调。与CREB敲低相似，CREB抑制剂KG-501降低了ALL细胞系以及原发性T-ALL样本中的白血病细胞活力并诱导凋亡，磷酸化CREB水平高的病例比磷酸化CREB水平低的病例更敏感。总之，这些体外研究结果支持了CREB在ALL细胞存活中的重要作用，并将该转录因子确定为潜在的治疗靶点。
