TUMOR SUPPRESSORS HEMATOPOIESIS AND LEUKEMIA

造血和白血病发生是一种发育现象，在这种发育过程中，多个基因的复杂相互作用导致有序分化或成熟阻滞和不受控制的增殖。虽然细胞、生化和转基因小鼠研究已经阐明了这些途径中的许多最终事件，但在造血和白血病发生中负责最基本发育决定的基因却不太明确。肿瘤抑制基因（TSGs），首先在遗传性人类癌症中被发现，很可能是这组基本基因之一。tsg是调节生长和分化的细胞通路的关键要素。特异性tsg已被证明在原发性人类白血病和白血病细胞系中发生突变或缺失。小鼠敲除模型和缺乏这些基因的患者表现出造血功能缺陷或发展为白血病。为了更好地了解肿瘤抑制基因在正常造血和白血病发生中的功能，我们选择斑马鱼作为模型，斑马鱼是一种结合生理和发育与强大遗传学的脊椎动物系统。我们计划创建缺乏已知TSGs的斑马鱼品系，并在这些品系中表征造血缺陷和白血病的发展。抑制或增强筛选突变，纠正缺陷或治愈白血病将导致这些途径中的其他基因的分离。在这个提议中描述的实验可能会发现在造血和白血病发生的控制中起关键作用的新蛋白。这些蛋白将成为治疗人类再生障碍性贫血、骨髓异常增生和白血病的潜在治疗靶点。

Hematopoiesis and leukemogenesis are developmental phenomena, in which complex interactions of multiple genes give rise to orderly differentiation or to maturation arrest and uncontrolled proliferation. While many of the terminal events in these pathways have been elucidated by cellular, biochemical and transgenic mouse studies, the genes responsible for the most fundamental developmental decisions in hematopoiesis and leukemogenesis have been less well-defined. Tumor suppressor genes (TSGs), first identified in hereditary human cancers, are likely to be among this group of fundamental genes. TSGs are key elements of cellular pathways that regulate growth and differentiation. Specific TSGs have been shown to be mutated or deleted in primary human leukemias and leukemic cell lines. Mouse knock-out models and patients deficient in several of these genes demonstrate defective hematopoiesis or develop leukemias. To better understand the function of tumor suppressor genes in normal hematopoiesis and leukemogenesis we have chosen as a model the zebrafish (Danio rerio), a vertebrate system that combines physiology and development with powerful genetics. We plan to create zebrafish strains deficient in known TSGs and to characterize hematopoietic defects and the development of leukemia in these strains. A suppressor or enhancer screen for mutations that correct the defects or cure the leukemia will lead to the isolation of additional genes in these pathways. The experiments described in this proposal are likely to identify novel proteins that play key roles in the control of hematopoiesis and the genesis of leukemia. These proteins will be potential therapeutic targets for the treatment of aplastic anemia, myelodysplasia and leukemia in humans.