Transgenic expression of PML/RAR alpha impairs myelopoiesis
Transgenic expression of PML/RAR alpha impairs myelopoiesis
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DOI：
10.1073/pnas.93.15.7900
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发表时间：
1996-07-23
影响因子：
11.1
通讯作者：
Dmitrovsky, E
中科院分区：
文献类型：
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作者：
Early, E;Moore, MAS;Dmitrovsky, E
在急性早幼粒细胞白血病中发现的易位将15号染色体上的早幼粒细胞白血病基因（PML）与17号染色体上的视黄酸受体α（RAR α）重排。这产生了融合转录物PML/RAR α，一种在不存在激素的情况下具有报道的显性负功能的转录因子。全反式维甲酸（RA）治疗急性早幼粒细胞白血病诱导的临床缓解与白血病细胞中PML/RAR α表达相关为了评估PML/RAR α在骨髓生成中的作用，对表达PML/RAR α的转基因小鼠进行工程改造。在转基因小鼠中表达由CD 11b启动子驱动的全长PML/RAR α cDNA。用逆转录PCR测定证实了在骨髓中的表达。PML/RAR α转基因小鼠和对照小鼠之间的基础总白色血细胞和粒细胞计数没有明显差异。CD 11b（+）骨髓细胞的细胞分选仪分析显示，转基因小鼠和对照小鼠中的CD 11b（+）群体相似。然而，在体外克隆生长试验进行外周血转基因小鼠与对照组显示显着减少骨髓祖细胞，特别是在那些响应于粒细胞/巨噬细胞集落刺激因子。粒细胞/巨噬细胞集落刺激因子和试剂盒配体共同治疗没有克服这种抑制作用。通过对这些小鼠进行亚致死剂量照射，显示体内骨髓生成受损。照射后，PML/RAR α转基因小鼠，与对照组相比，更迅速地降低外周白色血细胞和粒细胞计数。正如预期的那样，几乎所有对照小鼠（94.4%）在辐射中存活，但这种辐射对45.8%的PML/RAR α转基因小鼠是致命的。与对照组相比，转基因小鼠的致死率与更严重的白细胞减少症相关。维甲酸治疗照射的PML/RAR α小鼠增强粒细胞恢复。这些数据表明，由于PML/RAR α表达导致的异常骨髓生成是致癌转化的早期事件。
The translocation found in acute promyelocytic leukemia rearranges the promyelocytic leukemia gene (PML) on chromosome 15 with the retinoic acid receptor alpha (RAR alpha) on chromosome 17. This yields a fusion transcript, PML/RAR alpha, a transcription factor with reported dominant negative functions in the absence of hormone. Clinical remissions induced with all-trans retinoic acid (RA) treatment in acute promyelocytic leukemia are linked to PML/RAR alpha expression in leukemic cells. To evaluate the PML/RAR alpha role in myelopoiesis, transgenic mice expressing PML/RAR alpha were engineered. A full-length PML/RAR alpha cDNA driven by the CD11b promoter was expressed in transgenic mice. Expression was confirmed in the bone marrow with a reverse transcription PCR assay. Basal total white blood cell and granulocyte counts did not appreciably differ between PML/RAR alpha transgenic and control mice. Cell sorter analysis of Cd11b(+) bone marrow cells revealed similar CD11b(+) populations in transgenic and control mice. However, in vitro clonal growth assays performed on peripheral blood from transgenic versus control mice revealed a marked reduction of myeloid progenitors, especially in those responding to granulocyte/macrophage colony-stimulating factor. Granulocyte/macrophage colony-stimulating factor and kit ligand co-treatment did not overcome this inhibition. Impaired myelopoiesis in vivo was shown by stressing these mice with sublethal irradiation. Following irradiation, PML/RAR alpha transgenic mice, as compared with controls, more rapidly depressed peripheral white blod cell and granulocyte counts. As expected, nearly all control mice (94.4%) survived irradiation, yet this irradiation was lethal to 45.8% of PML/RAR alpha transgenic mice. Lethality was associated with more severe leukopenia in transgenic versus control mice. Retinoic acid treatment of irradiated PML/RAR alpha mice enhanced granulocyte recovery. These data suggest that abnormal myelopoiesis due to PML/RAR alpha expression is an early event in oncogenic transformation.