Dimerization of MLL fusion proteins immortalizes hematopoietic cells
Dimerization of MLL fusion proteins immortalizes hematopoietic cells
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DOI：
10.1016/s1535-6108(03)00214-9
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发表时间：
2003-09-01
期刊：
影响因子：
50.3
通讯作者：
Hess, JL
中科院分区：
文献类型：
--
作者：
Martin, ME;Milne, TA;Hess, JL
MLL融合蛋白可致白血病，但其机制尚不清楚。截断的MLL诱导二聚化使骨髓永生化，并对与Hox a7、a9和Meis1上调相关的髓细胞分化施加可逆阻断。二聚化的MLL和外显子复制的MLL都是有效的转录激活因子，这表明二聚化与MLL DNA结合域的部分串联复制之间存在联系。二聚化的MLL与Hox a9位点内的CpG岛结合的亲和力高于未二聚化的MLL。然而，MLL-AF9在体内不是二聚化的。数据支持MLL二聚化/外显子复制或转录激活子融合导致Hox基因上调并最终转化的模型。
MLL fusion proteins are leukemogenic, but their mechanism is unclear. Induced dimerization of a truncated MLL immortalizes bone marrow and imposes a reversible block on myeloid differentiation associated with upregulation of Hox a7, a9, and Meis1. Both dimerized MLL and exon-duplicated MLL are potent transcriptional activators, suggesting a link between dimerization and partial tandem duplication of DNA binding domains of MLL. Dimerized MLL binds with higher affinity than undimerized MLL to a CpG island within the Hox a9 locus. However, MLL-AF9 is not dimerized in vivo. The data support a model in which either MLL dimerization/exon duplication or fusion to a transcriptional activator results in Hox gene upregulation and ultimately transformation.