Mechanism(s) of Leukemogenesis in Genetically-Altered Mouse Models

白血病，这在儿童时期特别严重 病例，是遗传和环境相互作用的结果 造血组织功能障碍。公众健康担忧 苯是有理由的，因为它会释放到环境中 来自自然和工业来源，已经变得无处不在 在空气、水、土壤中，以及随后在食物和饮料中。 苯对人类和实验室啮齿动物都是致癌的。在… 高水平的苯暴露(&lt；30ppm)与 造血元素抑制导致再生障碍性贫血， 其次是骨髓增生异常综合征(MDS)，最终 白血病。长期暴露在相对较低水平下的影响 苯的含量是未知的。苯的实验动物模型 诱导白血病发生还没有成功地研究出来， 因此，苯致白血病的机制研究在以下几个方面得到了证实 缺乏明确的实验条件。利用基因上的 改良的小鼠品系Tg.AC，它携带两个可诱导的副本 病毒Harvey ras(v-H-ras)基因，我们已经能够证明 术后皮肤肿瘤和髓系白血病的诱发 皮肤暴露于高水平的苯。进一步的调查已经 显示局部应用苯诱导的抑制 红系(红细胞)和髓系(白细胞)成分 随之而来的是骨髓中的髓系白血病 侵入脾、肝、肺和外周血液。 白血病骨髓细胞移植到照射后的同基因骨髓细胞 非基因改变的宿主会形成病灶，表现出很高的 分化为成骨样细胞的比例 未成熟粒细胞，并表达可诱导的v-H-ras 转基因。目前，我们正在调查基因变化 与发生在苯中的这种转化相关联 曝光。苯的实验模型的建立 在短期生物测试中诱导白血病可能使我们能够 确定：(1)在这些条件下白血病发生的机制基础 实验条件和起作用的遗传因素 易感性；(2)干预和预防策略。

Leukemia, which is particularly severe in childhood cases, is the result of genetic and environmental interaction and dysfunction of the blood forming tissues. Public health concern over benzene is warranted because it is released into the environment from both natural and industrial sources and has become ubiquitous in air, water, soil, and, subsequently, in food and beverages. Benzene is carcinogenic to both humans and laboratory rodents. At high levels of exposure (< 30 ppm) benzene is associated with depression of blood forming elements leading to anaplastic anemia, followed by myelodysplastic syndrome (MDS) and, ultimately, to leukemia. The effect of long term exposure to relatively low levels of benzene is unknown. Experimental animal models of benzene induced leukemogenesis have not been successfully developed and, thus, mechanistic studies of benzene induced leukemogenesis under defined experimental conditions are lacking. Using the genetically altered mouse line Tg.AC, which carries two copies of an inducible viral Harvey ras (v-H-ras) gene, we have been able to demonstrate the induction of both skin tumors and myeloid leukemia after dermal exposure to high levels of benzene. Further investigation has revealed that the topical application of benzene induced suppression of both erythroid (red cell) and myeloid (white cell) components is followed by development of a myeloid leukemia in the bone marrow which invade the spleen, liver, lungs, and peripheral blood. Leukemia bone marrow cells transplanted to irradiated syngeneic non-genetically altered hosts develop foci, which show a high proportion of blast-like cells that undergo differentiation to immature granulocytes, and express the inducible v-H-ras transgene. Presently, we are investigating the genetic changes associated with this transformation that occur during benzene exposure. Development of an experimental model for benzene induced leukemia in a short term bioassay may allow us to determine: (1) a mechanistic basis for leukemogenesis under these experimental conditions and the genetic factors that play a role in susceptibility and (2) strategies for intervention and prevention.