白血病基因产物靶向治疗的基础和临床研究  

Basic and Clinical Studies of the Gene Product-Targeting Therapy Based on Leukemogenesis ——Editorial

作　　者：陈赛娟[1] 陈丽娟[1] 周光飚[1] 

机构地区：[1]上海第二医科大学附属瑞金医院

出　　处：《中国实验血液学杂志》2005年第1期1-8,共8页Journal of Experimental Hematology

摘　　要：全反式维甲酸 (ATRA)和三氧化二砷 (As2 O3)治疗急性早幼粒细胞性白血病 (APL)获得了很大成功 ,已经成为白血病靶向治疗研究的代表性模式。ATRA与As2 O3的作用靶点均为异常转录因子PML RARα,前者通过针对RARα ,而后者通过PMLSUMO化后使PML RARα致病蛋白降解 ,导致APL细胞分化和凋亡。ATRA与As2 O3联合治疗初发APL ,证实了两药的相互协同作用 ,获得了迄今为止成人急性白血病治疗的最好疗效。酪氨酸激酶抑制剂格力维 (Gleevec)在慢性粒细胞白血病 (CML)治疗中获得了成功。联合应用格力维与砷剂治疗CML已在临床和实验中初步证实其有效性 ,这一治疗方案是基于针对ABL异常的酪氨酸激酶活性与降解BCR ABL融合蛋白的双重靶向作用。白血病多靶点联合治疗的思路将进一步拓展至ANLL M2b型白血病 ,为该类白血病提供新的治疗方案 ,有可能使该类白血病获得更为有效的治疗效果。In the last twenty years, using all-trans retinoic acid (ATRA) as a differentiation inducer, Shanghai Institute of Hematology has achieved an important breakthrough in the treatment of acute promyelocytic leukemia (APL), which realized the theory of reversing phenotype of cells and provided a successful model of differentiation therapy in cancers. Our group first discovered in the world the variant chromosome translocation t(11;17)(q23;q21) of APL, and cloned the PML-RARα, PLZF-RARα and NPM-RARα fusion genes corresponding to the characterized chromosome translocations t(15;17); t(11;17) and t(5;17) in APL. Moreover, establishment of transgenic mice model of APL proved their effects on leukemogenesis. The ability of ATRA to modify the recruitment of nuclear receptor co-repressor with PML-RARα but not PLZF-RARα caused by the variant chromosome translocation elucidated the therapeutic mechanism of ATRA from the molecular level and provides new insight into transcription-modulating therapy. Since 1994, our group has successfully applied arsenic trioxide (As 2O 3) in treating relapsed APL patients, with the complete remission rate of 70%-80%. The molecular mechanism study revealed that As 2O 3 exerts a dose-dependent dual effect on APL. Low-dose As 2O 3 induced partial differentiation of APL cells, while the higher dose induced apoptosis. As 2O 3 binds ubiquitin like SUMO-1 through the lysine 160 of PML, resulting in the degradation of PML-RARα. Taken together, ATRA and As 2O 3 target the transcription factor PML-RARα, the former by retinoic acid receptor and the latter by PML sumolization, both induce PML-RARα degradation and APL cells differentiation and apoptosis. Because of the different acting pathways, ATRA and As 2O 3 have no cross-resistance and can be used as combination therapy. Clinical trial in newly diagnosed APL patients showed that ATRA/As 2O 3 in combination yields a longer disease-free survival time. With the median survival of 18 months, none of the 20 cases in combination treat

关 键 词：白血病 靶向治疗 AS2O3 ATRA APL 治疗方案 CML 融合蛋白 转录因子 基因产物 

分 类 号：R733[医药卫生—肿瘤] R730[医药卫生—临床医学]