Transcriptional Deregulation by MLL Fusion Proteins

描述（由申请人提供）：混合谱系的重排 白血病基因（MLL）与侵袭性淋巴样和髓样细胞相关 儿童和成人的白血病。MLL，与果蝇同源 Trithorax是一个不断增长的表观遗传转录调节因子家族之一 包括CBP、MOZ和与人类恶性肿瘤有关的IN 11。MLL融合到 超过25种不同的易位伴侣之一，通常共享 几乎没有序列同源性，将其转化为致白血病的癌蛋白。的 通过MLL融合蛋白的转化机制知之甚少 尽管它无疑涉及靶基因的转录失调。 研究这一功能的努力受到了缺乏知识的阻碍， 这些靶基因都排除了信号改变的研究， 转导途径，以及功能研究，以辨别机制， 在靶启动子处激活。我们现在已经确定了一个依赖c-MYC的 启动子被5种不同的MLL融合蛋白强烈反式激活， 以及通过MLL的二聚化或外显子重复形式， 在人类白血病中。我们的数据表明，MLL和易位的结构域 反式激活所需的伴侣也是转化所需的， 反式激活也依赖于ATP酶依赖的SWI/SNF 染色质重塑复合体我们的总体目标是更好地定义MLL如何 融合蛋白使靶基因的表达失调。（1）作用 MLL的二聚化和寡聚化的反式激活， 转化将被定义，和四个保守的突变的效果， 将评估MLL领域对这些功能的影响。2)MLL的直接目标 将鉴定融合蛋白。3)我们将确定MLL是否诱导 白血病是可逆的。4)SWI/SNF复合物在MLL融合中的作用 蛋白质的反式激活和转化将被探索。

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.