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: 6329005
• 负责人: STEPHAN W MORRIS
• 金额: $ 30.71万
• 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/6329005
• 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.

T(3；5)在骨髓增生异常综合征和急性髓系白血病中的作用 (AML)创造了一种融合产品，其中氨基末端 核磷蛋白(NPM)，一种核仁穿梭蛋白，与新的 蛋白骨髓增生异常/髓系白血病因子1(MLF1)。新能源管理 NPM-MLF1的一部分包含一个寡聚基序，它介导 自缔合、与正常NPM的缔合和核靶向性； 这些(和其他)NPM功能在NPM-MLF1介导中的重要性 MDS和AML未知。正常的细胞质MLF1蛋白，它 缺乏公认的功能基序，在一些白血病细胞中表达 但不在t(3；5)阳性细胞中；MLF1在正常中的作用 造血功能尚未确定。NPM-MLF1可抑制G-CSF- 介导的生存，因此，分化的髓系前体 细胞以一种与提出的MDS发病机制一致的方式 进展为急性髓细胞白血病可能需要更多的突变 与NPM-MLF1。了解NPM-MLF1在发病中的作用 在MDS和AML中，NPM和MLF1中的功能关键基序 介导其阻断髓系细胞能力的融合部分 首先将确定生存/分化。接下来，假设 NPM-MLF1干扰造血发育而产生MDS AML将在编程为表达融合的小鼠身上进行测试；作为一种 推论，急性髓系白血病诱导过程中协同突变的必要性 通过NPM-MLF1将被确定，如果需要，涉及的基因将 被指认出来。最后，MLF1在正常生长和发育中的作用 将对发展进行定义，以更好地了解其变化 通过确定Mlf1在胎儿中的表达模式产生MDS和AML 和成年小鼠，通过有针对性地破坏基因，并通过评估 Mlf1缺失或异常表达对造血的影响 胚胎干细胞体外分化的研究。这些研究应该会产生 对NPM-MLF1扰乱的调控途径有价值的洞察 骨髓增生异常(白血病前期)细胞，并可能进入病理生物学 一般的急性髓系白血病。