NUP98-HOXA9 AND AML

NUP98-HOXA9 和 AML

• 批准号: 2562407
• 负责人: JAN M. VAN DEURSEN
• 金额: $ 24.82万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 1999-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2562407
• 关键词: 3T3 cells; acute myelogenous leukemia; animal breeding; disease /disorder etiology; fusion gene; gene expression; genetic manipulation; laboratory mouse; nucleic acid sequence; phenotype; protein isoforms; protein structure function; tissue /cell culture; tissue mosaicism; transcription factor

DESCRIPTION: (adapted from the investigator's abstract) The t(7;11) in patients with acute myeloid leukemia (AML) generates a fusion gene encoding the amino-terminal NUP98, an FG repeat-containing nuclear pore complex protein (NPC), and the carboxy-terminus of HOXA9, a homeotic transcription factor. The NUP98 portion of NUP98-HOXA9 contains 37 of the 38 FG repeat motif of NUP98. The HOXA9 part contains the HOXA9 DNA-binding domain and a TRP-containing motif that mediates interactions between HOXA9 and other transcription factors. The long term objective is to understand the exact mechanism by which NUP98-HOXA9 contributes to leukemia. To achieve this goal, the functionally critical motifs in the NUP98 and HOXA9 portions of NUP98-HOXA9 that mediate its ability to transform NIH3T3 cell will be defined, as will the proteins that interact with these motifs. The ability of each NUP98-HOXA9 isoform to induce AML in vivo will be tested by genetically engineering mice to express the chimeric proteins. Further, these mice will be bred onto a BXH2 genetic background to identify mutations that cooperate with NUP98-HOXA9 to induce AML. Finally, the normal in vivo functions of NUP98 and HOXA9 will be studied by examining phenotypic effects of loss- or gain-of-function mutations in mice. These studies should further our understanding of the molecular mechanism of oncogenesis in an expanding subgroup o AML patients with translocations that link nucleoporins to nuclear proteins.

描述：（改编自研究者摘要） 急性髓性白血病（AML）患者产生一种融合基因， 氨基末端NUP 98，一种含有FG重复核孔复合物 蛋白（NPC）和HOXA 9的羧基末端，HOXA 9是一种同源异型转录蛋白， 因子 NUP 98-HOXA 9的NUP 98部分含有38个FG重复序列中的37个 NUP 98的基序。 HOXA 9部分含有HOXA 9 DNA结合结构域和一个 含有TRP的基序介导HOXA 9与其他 转录因子 长期目标是了解 NUP 98-HOXA 9导致白血病的机制。 实现这一 目标，NUP 98和HOXA 9部分的功能关键基序， NUP 98-HOXA 9介导其转化NIH 3 T3细胞的能力， 与这些基序相互作用的蛋白质也将如此。 的能力 每种NUP 98-H 0XA 9同种型在体内诱导AML的能力将通过 对小鼠进行基因工程改造以表达嵌合蛋白。 此外，本发明还 这些小鼠将在BXH 2基因背景下繁殖，以鉴定突变 与NUP 98-HOXA 9协同诱导AML。 最后，正常体内 NUP 98和HOXA 9的功能将通过检查表型效应来研究 功能丧失或获得突变的基因。 这些研究应 进一步了解肿瘤发生的分子机制， 具有连接核孔蛋白的易位的AML患者的扩展亚组 核蛋白质。