NUP98-HOXA9 AND AML

描述：(改编自调查员摘要)中的t(7；11) 急性髓系白血病(AML)患者产生编码融合基因 氨基末端NUP98，一种含有FG重复序列的核孔复合体 蛋白(NPC)和HOXA9的羧基末端，一个同源异型转录 因素。NUP98-HOXA9的NUP98部分包含38个FG重复序列中的37个 NUP98的主题。HOXA9部分包含HOXA9 DNA结合域和一个 介导HOXA9与其他基因相互作用的含Trp基序 转录因子。长期目标是了解准确的 NUP98-HOXA9在白血病中的作用机制要做到这一点 Goal，NUP98和HOXA9部分中的功能关键基序 介导其转化NIH3T3细胞能力的NUP98-HOXA9将是 定义，以及与这些基序相互作用的蛋白质。一种能力 每种NUP98-HOXA9亚型在体内诱导AML的测试将通过 通过基因工程使小鼠表达嵌合蛋白。此外， 这些小鼠将被培育到Bxh2的遗传背景上，以识别突变 与NUP98-HOXA9协同诱导AML。最后，活体内的正常 将通过检测表型效应来研究NUP98和HOXA9的功能 小鼠功能丧失或功能获得突变的可能性。这些研究应该 进一步加深对肝癌发生的分子机制的认识 核孔素相关易位的AML患者亚群扩大 核蛋白。

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.