Transcriptional Deregulation by MLL Fusion Proteins

描述(申请人提供)：混合血统的重新安排 白血病基因(MLL)与侵袭性淋巴和髓系相关 儿童和成人都患有白血病。与果蝇同源的MLL Trithorax，是一个日益增长的表观遗传转录调控家族之一 包括与人类恶性肿瘤有关的CBP、MOZ和IN11。MLL与TO的融合 超过25个不同的移位合作伙伴之一，这些合作伙伴通常共享 小序列同源性，将其转化为白血病致癌蛋白。这个 MLL融合蛋白的转化机制尚不清楚 尽管它无疑涉及到对目标基因的转录放松管制。 由于缺乏对这一功能的了解，研究这一功能的努力受到了阻碍 靶向基因既排除了对信号变化的研究 转导途径，以及识别机制的功能研究 在目标推动者处激活。我们现在已经确定了一种c-myc依赖的 启动子被5种不同的MLL融合蛋白强烈反式激活 以及类似于那些发生的MLL的二聚化或外显子复制形式 在人类白血病中。我们的数据表明MLL和易位的结构域 转型也需要激活所需的合作伙伴，以及 此外，这种反式激活依赖于ATPase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 融合蛋白解除了对靶基因表达的调控。为此，1)角色 反式激活中MLL的二聚化和寡聚化 将对转化进行定义，并对四种突变的效果进行保守 将评估MLL在这些功能上的域。2)MLL的直接目标 融合蛋白将被鉴定出来。3)我们将确定MLL是否会导致 白血病是可逆的。4)SWI/SNF复合体在MLL融合中的作用 将探索蛋白质的反式激活和转化。

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.