So Chi Wai, Lin Min, Ayton Paul M, Chen Everett H, Cleary Michael L
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cancer Cell. 2003 Aug;4(2):99-110. doi: 10.1016/s1535-6108(03)00188-0.
MLL is a histone methyltransferase that can be converted into an oncoprotein by acquisition of transcriptional effector domains following heterologous protein fusions with a variety of nuclear transcription factors, cofactors, or chromatin remodeling proteins in acute leukemias. Here we demonstrate an alternative mechanism for activation of MLL following fusions with proteins (AF1p/Eps15 and GAS7) that normally reside in the cytoplasm. The coiled-coil oligomerization domains of these proteins are necessary and sufficient for leukemogenic transformation induced by the respective MLL fusion proteins. Furthermore, homodimerization of MLL by synthetic dimerization modules mimics bona fide MLL fusion proteins resulting in Hox gene activation and enhanced self-renewal of hematopoietic progenitors. Our studies support an oligomerization-dependent mechanism for oncogenic conversion of MLL, presumably in part by recruitment of accessory factors through the dimerized MLL moiety of the chimeric protein.
MLL是一种组蛋白甲基转移酶，在急性白血病中，它与多种核转录因子、辅因子或染色质重塑蛋白发生异源蛋白融合后，通过获得转录效应结构域可转化为癌蛋白。在此，我们展示了MLL与通常位于细胞质中的蛋白质（AF1p/Eps15和GAS7）融合后激活的另一种机制。这些蛋白质的卷曲螺旋寡聚化结构域对于由各自的MLL融合蛋白诱导的白血病转化是必要且充分的。此外，通过合成二聚化模块使MLL同源二聚化可模拟真正的MLL融合蛋白，导致Hox基因激活并增强造血祖细胞的自我更新能力。我们的研究支持MLL致癌转化的寡聚化依赖性机制，推测部分是通过嵌合蛋白二聚化的MLL部分募集辅助因子实现的。
