The function of I(3)mbt in hematopoietic cancers

描述（由申请人提供）：我们最近通过外显子捕获方法分离了人类l(3)mbt基因，该基因位于20号染色体长臂（20q）上，位于血液病恶性肿瘤中经常缺失的区域。人l(3)mbt蛋白与果蝇致死性恶性脑肿瘤[l(3)mbt]蛋白同源，均属于转录调控蛋白多梳群（polycomb group, PcG）家族；PcG蛋白在维持抑制关键基因如同源盒和细胞周期调控基因中起着至关重要的作用。PcG基因表达或功能异常已被证明在淋巴瘤和其他癌症的发生或进展中起关键作用。为了更完整地确定人类l(3)mbt基因在血液病中的作用，我们建议明确l(3)mbt的生物学活性和作用机制。为了表征l(3)mbt的生物学效应，我们将在造血细胞和Ras转化的NIH 3T3细胞中表达野生型和突变型的l(3)mbt。我们还将通过生成l(3)mbt条件敲除小鼠并分析其表型来评估l(3)mbt的缺乏如何影响造血。我们将通过鉴定l(3)mbt相互作用蛋白和含有l(3)mbt蛋白的多蛋白复合物，以及使用微阵列技术鉴定髓细胞中真正的1(3)mbt靶基因，来确定其作用机制。我们还将对l(3)mbt蛋白的不同结构域进行仔细的结构功能分析，以评估它们在转录调控特性、相关生化活性和生物学效应中的作用。PcG蛋白家族越来越多地与癌变有关，这些研究将深入了解l(3)mbt在血液恶性肿瘤中的作用。

DESCRIPTION (provided by applicant): We recently isolated the human l(3)mbt gene by exon trapping based on its location on the long arm of chromosome 20 (20q), within a region frequently deleted in hematologic malignancies. The human l(3)mbt protein is homologous to the Drosophila lethal malignant brain tumor [l(3)mbt] protein, and both belong to the polycomb group (PcG) family of transcriptional regulatory proteins; PcG proteins play vital roles in the maintenance of repression of key genes such as homeobox-containing and cell cycle regulatory genes. Abnormalities in the expression or function of PcG genes have been shown to play a key role in the development or progression of lymphomas and other cancers. To more completely define the role of the human l(3)mbt gene in hematologic cancers, we propose to define the biologic activities and mechanism of action of l(3)mbt. To characterize the biological effects of l(3)mbt we will express wild type and mutant forms of l(3)mbt in hematopoietic cells, and in Ras transformed NIH 3T3 cells. We will also assess how the lack of l(3)mbt affects hematopoiesis by generating l(3)mbt conditional knock-out mice and analyzing their phenotype. We will define its mechanism of action by identifying l(3)mbt interacting proteins and the multi-protein complex that contains the l(3)mbt protein, and by identifying true 1(3) mbt target genes in myeloid cells, using microarray technology. We will also conduct a careful structure-function analysis of the distinct domains in the l(3)mbt protein to assess their role in its transcriptional regulatory properties, its associated biochemical activities and its biological effects. The PcG family of proteins is being increasingly implicated in carcinogenesis, and these studies will provide insights into the role that l(3)mbt plays in hematologic malignancies.