PLZF-RARα/RARα-PLZF双阳性转基因小鼠发生白血病模型研究  

hCG-PLZF-RARα/hCG-RARα-PLZF Transgenic Mice Developing into Leukemia

作　　者：陈丽娟[1] 董颖[1] 陈思宇[1] 张龙[1] 周光飚[1] 陈冰[1] 王龙[1] 陈竺[1] 陈赛娟[1] 

机构地区：[1]上海第二医科大学附属瑞金医院,上海血液学研究所,医学基因组学国家重点实验室,上海200025

出　　处：《中国实验血液学杂志》2005年第6期924-931,共8页Journal of Experimental Hematology

基　　金：国家自然科学基金资助(30300139);上海市博士后科研资助计划资助(2003-16)

摘　　要：本研究目的是从生物整体水平上研究PLZFRARα/RARαPLZF双融合基因的表达在急性早幼粒细胞白血病(APL)发病中的作用及发病机制。通过交配建立PLZFRARα/RARαPLZF双阳性转基因小鼠(TM)模型;采用PCR、RTPCR方法检测融合基因的整合和表达;应用血象、骨髓象、病理和流式细胞术等对疾病表型进行检测分析;并观察全反式维甲酸(ATRA)或ATRA与tricostatinA(TSA)联合用药对PLZFRARα/RARαPLZF双阳性转基因小鼠骨髓细胞的作用。结果表明,在近18个月的时间观察到51只PLZFRARα/RARαPLZF双阳性转基因小鼠中有5只小鼠发病,发病率约10%,与我所同期的仅PLZFRARα转基因阳性小鼠11.3%的发病率相似。发病时间均在6月龄以后,与PLZFRARα转基因阳性发病小鼠相比示提前,但疾病表型不同,2只(40%)为急性早幼粒细胞白血病(APL)改变,3只(60%)为慢性粒细胞白血病(CML)改变。ATRA处理组的骨髓细胞形态无改变,而ATRA+TSA组骨髓原始细胞核浆比例降低,染色质固缩,呈现粒细胞分化趋势。结论PLZFRARα/RARαPLZFTM小鼠发病存在异质性,其骨髓细胞对ATRA无反应,而ATRA与TSA联合用药可诱导骨髓原始早幼粒细胞分化。To investigate the potential role and the mechanism of PLZF-RARα/RARα-PLZF double fusion gene in the pathogenesis of acute promyelocytic leukemia （APL） in vivo at systematic biological level, PLZF-RARα /RARα- PLZF double transgenic mouse model was established by intercross; the integration and expression of fusion genes were analyzed by PCR and RT-PCR; the disease phenotype was detected by morphological and pathological examination of peripheral blood and bone marrow cells, as well as flow cytometry assays ; the effects of ATRA with or without tricostatin A on bone marrow blast cells from PLZF-RARα/ RARα-PLZF double TM were observed. The results showed that leukemia occured in 5 PLZF-RARα/RARα-PLZF double TM 7, 7, 9,11 and 11 months respectively, out of them two （40%） with classic APL features, the others （60%） with chronic myeloid leukemia through an observation period of 18 months. The leukemia ocurrence of PLZF-RARa/RARcx-PLZF TM was about 10%, which was similar to PLZF-RARα TM as that reported before. The latency was over 6 months, not earlier than PLZF-RARα TM only. No morphologic changes of PLZF-RARα/RARα-PLZF double TM blast cells to ATRA were observed, but increased cytoplasmic-nuclear ratio and nuclear condensation in bone marrow blast cells were found in combination of ATRA with tricostatin A. It is concluded that PLZF-RARα/RARα-PLZF double fusion gene transgenic mice have heterogeneity of pathogenesis. HDAC inhibitors such as trichostatin A, in combination with ATRA, induce differentiation of the blast/promyelocytic cells from PLZF-RARα / RARα -PLZF double TM, but not ATRA alone.

关 键 词：PLZF-RARα/RARα-PLZF 急性早幼粒细胞白血病 慢性粒细胞白血病 转基因小鼠 

分 类 号：R733.7[医药卫生—肿瘤]