Ge Dong-zheng, Sheng Yan, Cai Xun
1] Shanghai Institute of Hematology and State Key Laboratory of Medical Genomics, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China [2] Department of Hematology, Peace Hospital of Changzhi Medical Colledge, Changzhi 046000, China.
Shanghai Institute of Hematology and State Key Laboratory of Medical Genomics, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Sci Rep. 2014 Apr 28;4:4821. doi: 10.1038/srep04821.
All-trans retinoic acid (ATRA) resistance has been a critical problem in acute promyelocytic leukemia (APL) relapsed patients. In ATRA resistant APL cell lines NB4-R1 and NB4-R2, the combination of staurosporine and ATRA synergized to trigger differentiation accompanied by significantly enhanced protein level of CCAAT/enhancer binding protein ε (C/EBPε) and C/EBPβ as well as the phosphorylation of mitogen-activated protein (MEK) and extracellular signal-regulated kinase (ERK). Furthermore, attenuation of the MEK activation blocked not only the differentiation but also the increased protein level of C/EBPε and C/EBPβ. Taken together, we concluded that the combination of ATRA and staurosporine could overcome differentiation block via MEK/ERK signaling pathway in ATRA-resistant APL cell lines.
全反式维甲酸（ATRA）耐药一直是急性早幼粒细胞白血病（APL）复发患者面临的关键问题。在对ATRA耐药的APL细胞系NB4-R1和NB4-R2中，星形孢菌素与ATRA联合使用可协同触发分化，同时CCAAT/增强子结合蛋白ε（C/EBPε）和C/EBPβ的蛋白水平显著升高，以及丝裂原活化蛋白（MEK）和细胞外信号调节激酶（ERK）的磷酸化。此外，MEK激活的减弱不仅阻断了分化，还阻断了C/EBPε和C/EBPβ蛋白水平的升高。综上所述，我们得出结论，ATRA与星形孢菌素联合使用可通过MEK/ERK信号通路克服ATRA耐药APL细胞系中的分化阻滞。
