Transcriptional Deregulation by MLL Fusion Proteins

MLL 融合蛋白的转录失调

• 批准号: 7034595
• 负责人: Jay L. Hess
• 金额: $ 25.96万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7034595
• 关键词: carcinogenesis; cell line; cell transformation; chimeric proteins; genetic promoter element; genetic transcription; laboratory mouse; lymphocytic leukemia; microarray technology; myelogenous leukemia; neoplasm /cancer genetics; oncoproteins; polymerization; protooncogene; site directed mutagenesis

DESCRIPTION (provided by applicant): Rearrangements of the mixed lineage leukemia gene (MLL) are associated with aggressive lymphoid and myeloid leukemias in both children and adults. MLL, which is homologous to Drosophila Trithorax, is one of a growing family of epigenetic regulators of transcription including CBP, MOZ, and IN11 implicated in human malignancies. Fusion of MLL to one of more than 25 different translocation partners, which in general share little sequence homology, converts it into a leukemogenic oncoprotein. The mechanism of transformation by MLL fusion proteins is poorly understood although it undoubtedly involves transcriptional deregulation of target genes. Efforts to study this function has been hampered by the lack of knowledge of target genes that has both precluded studies of alterations in signal transduction pathways, as well as functional studies to discern mechanisms of activation at target promoters. We have now identified a c-MYC-dependent promoter that is strongly transactivated by 5 different MLL fusion proteins as well as by dimerized or exon-duplicated forms of MLL resembling those occurring in human leukemias. Our data indicate that domains of MLL and translocation partners required for transactivation are also required for transformation, and also that transactivation is dependent on the ATPase-dependent SWI/SNF chromatin remodeling complex. Our overall goal is to better define how MLL fusion proteins deregulate expression of target genes. To this end 1) The role of dimerization and oligomerization of MLL in transactivation and transformation will be defined, and the effect of mutagenesis of four conserved domains of MLL on these functions will be assessed. 2) Direct targets of MLL fusion proteins will be identified. 3) We will determine if MLL induced leukemia is reversible. 4) The role of the SWI/SNF complex in MLL fusion protein transactivation and transformation will be explored.

描述（由申请人提供）：混合血统的重排 白血病基因（MLL）与侵袭性淋巴和髓样有关 儿童和成人的白血病。 MLL，与果蝇同源 Trithorax是不断增长的表观遗传调节剂的家族之一 包括CBP，MOZ和IN11涉及人类恶性肿瘤。 MLL的融合 一般共享的25多个不同的转运伙伴之一 小序列同源性，将其转化为白血病性癌蛋白。这 MLL融合蛋白转化的机制知之甚少 尽管它无疑涉及靶基因的转录放松管制。 缺乏了解 靶基因既排除了信号改变的研究 转导途径以及功能研究以辨别 目标启动子激活。我们现在已经确定了c-myc依赖性 启动子被5种不同的MLL融合蛋白强烈反式激活为 以及通过类似于发生的MLL的二聚体或外显子的形式 在人类白血病中。我们的数据表明MLL和易位的域 转变还需要进行反式激活所需的伙伴，并且 同样，反式激活取决于依赖ATPase的SWI/SNF 染色质重塑复合物。我们的总体目标是更好地定义如何MLL 融合蛋白不导致靶基因的表达。为此结束1）角色 MLL在反式激活中的二聚化和低聚 将定义转换，以及四个保守的诱变的影响 将评估这些功能上MLL的域。 2）MLL的直接目标 将确定融合蛋白。 3）我们将确定是否诱导了MLL 白血病是可逆的。 4）SWI/SNF复合物在MLL融合中的作用 将探索蛋白质反式激活和转化。