Okada Yuki, Feng Qin, Lin Yihui, Jiang Qi, Li Yaqiang, Coffield Vernon M, Su Lishan, Xu Guoliang, Zhang Yi
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Cell. 2005 Apr 22;121(2):167-78. doi: 10.1016/j.cell.2005.02.020.
Epigenetic modifications play an important role in human cancer. One such modification, histone methylation, contributes to human cancer through deregulation of cancer-relevant genes. The yeast Dot1 and its human counterpart, hDOT1L, methylate lysine 79 located within the globular domain of histone H3. Here we report that hDOT1L interacts with AF10, an MLL (mixed lineage leukemia) fusion partner involved in acute myeloid leukemia, through the OM-LZ region of AF10 required for MLL-AF10-mediated leukemogenesis. We demonstrate that direct fusion of hDOT1L to MLL results in leukemic transformation in an hDOT1L methyltransferase activity-dependent manner. Transformation by MLL-hDOT1L and MLL-AF10 results in upregulation of a number of leukemia-relevant genes, such as Hoxa9, concomitant with hypermethylation of H3-K79. Our studies thus establish that mistargeting of hDOT1L to Hoxa9 plays an important role in MLL-AF10-mediated leukemogenesis and suggests that the enzymatic activity of hDOT1L may provide a potential target for therapeutic intervention.
表观遗传修饰在人类癌症中发挥着重要作用。其中一种修饰，即组蛋白甲基化，通过与癌症相关基因的失调而导致人类癌症。酵母Dot1及其人类同源物hDOT1L可使位于组蛋白H3球状结构域内的赖氨酸79发生甲基化。在此，我们报告hDOT1L通过MLL-AF10介导的白血病发生所需的AF10的OM-LZ区域与AF10相互作用，AF10是一种参与急性髓性白血病的MLL（混合谱系白血病）融合伴侣。我们证明hDOT1L与MLL的直接融合以hDOT1L甲基转移酶活性依赖的方式导致白血病转化。MLL-hDOT1L和MLL-AF10介导的转化导致许多白血病相关基因（如Hoxa9）上调，同时伴有H3-K79的高甲基化。因此，我们的研究表明hDOT1L错误靶向Hoxa9在MLL-AF10介导的白血病发生中起重要作用，并表明hDOT1L的酶活性可能为治疗干预提供潜在靶点。
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