TUMOR SUPPRESSORS HEMATOPOIESIS AND LEUKEMIA

造血和白血病发生是发育现象，其中多个基因的复杂相互作用引起有序分化或成熟停滞和不受控制的增殖。 虽然这些途径中的许多终末事件已通过细胞、生物化学和转基因小鼠研究阐明，但负责造血和白血病发生中最基本的发育决定的基因还不太明确。 肿瘤抑制基因（TSGs），首先在遗传性人类癌症中发现，很可能是这组基础基因之一。 TSG是调节生长和分化的细胞途径的关键元件。 已显示在原发性人类白血病和白血病细胞系中特异性TSG突变或缺失。小鼠基因敲除模型和这些基因中的几个缺陷的患者表现出造血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，我们选择了斑马鱼（Danio rerio）作为模型，这是一种将生理学和发育与强大的遗传学相结合的脊椎动物系统。 我们计划创建已知TSG缺陷的斑马鱼品系，并表征这些品系中的造血缺陷和白血病的发展。 通过筛选抑制子或增强子来纠正缺陷或治愈白血病的突变，将导致在这些途径中分离出额外的基因。 本提案中描述的实验可能会发现在造血控制和白血病发生中起关键作用的新蛋白质。 这些蛋白将成为治疗人类再生障碍性贫血、骨髓增生异常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.