Chen Li-Juan, Dong Ying, Chen Si-Yu, Zhang Long, Zhou Guang-Biao, Chen Bing, Wang Long, Chen Zhu, Chen Sai-Juan
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, The Shanghai Second Medical University, Shanghai 200025, China.
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2005 Dec;13(6):924-31.
To investigate the potential role and the mechanism of PLZF-RARalpha/RARalpha-PLZF double fusion gene in the pathogenesis of acute promyelocytic leukemia (APL) in vivo at systematic biological level, PLZF-RARalpha/RARalpha-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-RARalpha/RARalpha-PLZF double TM were observed. The results showed that leukemia occurred in 5 PLZF-RARalpha/RARalpha-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 occurrence of PLZF-RARalpha/RARalpha-PLZF TM was about 10%, which was similar to PLZF-RARalpha TM as that reported before. The latency was over 6 months, not earlier than PLZF-RARalpha TM only. No morphologic changes of PLZF-RARalpha/RARalpha-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-RARalpha/RARalpha-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-RARa/RARa-PLZF double TM, but not ATRA alone.
为了在系统生物学水平上研究PLZF-RARα/RARα-PLZF双融合基因在急性早幼粒细胞白血病（APL）发病机制中的潜在作用及机制，通过杂交建立了PLZF-RARα/RARα-PLZF双转基因小鼠模型；采用PCR和RT-PCR分析融合基因的整合与表达情况；通过外周血和骨髓细胞的形态学及病理学检查以及流式细胞术检测疾病表型；观察全反式维甲酸（ATRA）联合或不联合曲古抑菌素A对PLZF-RARα/RARα-PLZF双转基因小鼠骨髓原始细胞的影响。结果显示，在18个月的观察期内，5只PLZF-RARα/RARα-PLZF双转基因小鼠分别于7、7、9、11和11个月发生白血病，其中2只（40%）具有典型APL特征，其余（60%）表现为慢性髓细胞白血病。PLZF-RARα/RARα-PLZF双转基因小鼠的白血病发生率约为10%，与之前报道的PLZF-RARα转基因小鼠相似。潜伏期超过6个月，并不早于PLZF-RARα转基因小鼠。未观察到PLZF-RARα/RARα-PLZF双转基因小鼠原始细胞对ATRA的形态学变化，但ATRA联合曲古抑菌素A时，骨髓原始细胞的细胞质与细胞核比例增加且出现核浓缩。结论是PLZF-RARα/RARα-PLZF双融合基因转基因小鼠具有发病机制的异质性。曲古抑菌素A等组蛋白去乙酰化酶抑制剂联合ATRA可诱导PLZF-RARα/RARα-PLZF双转基因小鼠的原始/早幼粒细胞分化，但单独使用ATRA则无此作用。
