NPM/MLF1 IN LEUKEMIA AND NORMAL DEVELOPMENT

NPM/MLF1 在白血病和正常发育中的作用

• 批准号: 6124435
• 负责人: STEPHAN W MORRIS
• 金额: $ 29.81万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-15 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6124435
• 关键词: acute myelogenous leukemia; cell differentiation; dyserythropoietic anemia; gene expression; gene targeting; genetically modified animals; laboratory mouse; neoplastic process; protein metabolism; protein structure function

The t(3;5) in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) creates a fusion product in which the amino-terminus of nucleophosmin (NPM), a nucleolar shuttle protein, is linked to the novel protein myelodysplasia/myeloid leukemia factor 1 (MLF1). The NPM portion of NPM-MLF1 contains an oligomerization motif that mediates self- association, association with normal NPM, and nuclear targeting; the importance of these (and other) NPM functions in NPM-MLF1-mediated MDS and AML is unknown. The normally cytoplasmic MLF1 protein, which lacks recognized functional motifs, is expressed in some leukemic cell lines but not in t(3;5)- positive cells; the role of MLF1 in normal hematopoiesis has not been determined. NPM-MLF1 can inhibit the G-CSF- mediated survival and, hence, the differentiation of myeloid precursor cells in a manner consistent with the proposed pathogenesis of MDS; MDS progression to AML probably requires additional mutations that cooperate with NPM-MLF1. To understand how NPM-MLF1 contributes to the genesis of MDS and AML, the funtionally -critical motifs in the NPM and MLF1 portions of the fusion that mediate its ability to block myeloid cell survival/differentiation will first be identified. Next, the hypothesis that NPM-MLF1 interferes with hematopoietic development to produce MDS and AML will be tested in mice programmed to express the fusion; as a corollary, the necessity for cooperating mutations in the induction AML by NPM-MLF1 will be determined and, if required, the involved genes will be identified. Finally, the role of MLF1 in normal growth and development will be defined to better understand how its alteration produces MDS and AML by determining the Mlf1 expression pattern in fetal and adult mice, by targeted disruption of the gene, and by assessing the effects of Mlf1 absence, or its aberrant expression, on hematopoietic differentiation of ES cells in vitro. These studies should yield valuable insight into the regulatory pathways disrupted by NPM-MLF1 in myelodysplastic (preleukemic) cells, and perhaps into the pathobiology of AML in general.

骨髓增生异常综合征与急性髓系白血病t（3;5）的研究 (AML)产生融合产物，其中 核仁磷酸蛋白（NPM），一种核仁穿梭蛋白，与新的 蛋白质骨髓增生异常/髓性白血病因子1（MLF 1）。 国家预防机制 NPM-MLF 1的一部分含有介导 自缔合、与正常NPM的缔合以及核靶向; 这些（和其他）NPM功能在NPM-MLF 1介导的 MDS和AML是未知的。 正常的细胞质MLF 1蛋白， 缺乏公认的功能基序，在某些白血病细胞中表达 在t（3;5）阳性细胞中没有; MLF 1在正常细胞中的作用 造血功能尚未确定。NPM-MLF 1可以抑制G-CSF- 介导的生存，因此，髓样前体细胞的分化 与MDS的发病机制一致的方式 AML的进展可能需要额外的突变， NPM-MLF1 为了了解NPM-MLF 1如何有助于发生 在MDS和AML中，NPM和MLF 1中的功能关键基序 介导其阻断骨髓细胞增殖能力的融合部分 将首先鉴定存活/分化。 接下来，假设 NPM-MLF 1干扰造血发育产生MDS 和AML将在编程表达融合体的小鼠中进行测试;作为一个实验， 推论，诱导AML中合作突变的必要性 通过NPM-MLF 1将被确定，如果需要，所涉及的基因将 被识别。 最后，MLF 1在正常生长和 发展将被定义，以更好地了解如何改变 通过确定胎儿中Mlf 1的表达模式产生MDS和AML 和成年小鼠，通过靶向破坏基因，并通过评估 Mlf 1缺失或其异常表达对造血细胞的影响 ES细胞的体外分化。 这些研究应该会产生 对NPM-MLF 1破坏的调节途径的有价值的见解， 骨髓增生异常（白血病前期）细胞，也许进入病理生物学 一般来说，AML