Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Genes Dev. 2018 Mar 1;32(5-6):341-346. doi: 10.1101/gad.311639.118. Epub 2018 Mar 21.
The mixed-lineage leukemia (MLL)-AF10 fusion oncoprotein recruits DOT1L to the homeobox A () gene cluster through its octapeptide motif leucine zipper (OM-LZ), thereby inducing and maintaining the MLL-AF10-associated leukemogenesis. However, the recognition mechanism between DOT1L and MLL-AF10 is unclear. Here, we present the crystal structures of both apo AF10 and its complex with the coiled-coil domain of DOT1L. Disruption of the DOT1L-AF10 interface abrogates MLL-AF10-associated leukemic transformation. We further show that zinc stabilizes the DOT1L-AF10 complex and may be involved in the regulation of the gene expression. Our studies may also pave the way for the rational design of therapeutic drugs against -rearranged leukemia.
混合谱系白血病（MLL）-AF10 融合癌蛋白通过其八肽基序亮氨酸拉链（OM-LZ）募集 DOT1L 到同源盒 A（）基因簇，从而诱导和维持 MLL-AF10 相关的白血病发生。然而，DOT1L 和 MLL-AF10 之间的识别机制尚不清楚。在这里，我们展示了 apo AF10 及其与 DOT1L 卷曲螺旋结构域复合物的晶体结构。破坏 DOT1L-AF10 界面可消除 MLL-AF10 相关的白血病转化。我们进一步表明，锌稳定 DOT1L-AF10 复合物，并且可能参与调节基因的表达。我们的研究也可能为针对基因重排白血病的合理设计治疗药物铺平道路。
