hDOT1L links histone methylation to leukemogenesis
hDOT1L links histone methylation to leukemogenesis
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DOI：
10.1016/j.cell.2005.02.020
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发表时间：
2005-04-22
期刊：
影响因子：
64.5
通讯作者：
Zhang, Y
中科院分区：
文献类型：
--
作者：
Okada, Y;Feng, Q;Zhang, Y
表观遗传修饰在人类癌症中发挥着重要作用。其中一种修饰是组蛋白甲基化，它通过癌症相关基因的失调而导致人类癌症。酵母 Dot1 及其人类对应物 hDOT1L 将位于组蛋白 H3 球状结构域内的赖氨酸 79 甲基化。在这里，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是一种参与急性髓系白血病的MLL（混合谱系白血病）融合伴侣。我们证明 hDOT1L 与 MLL 的直接融合会以 hDOT1L 甲基转移酶活性依赖性方式导致白血病转化。 MLL-hDOT1L 和 MLL-AF10 的转化导致许多白血病相关基因（例如 Hoxa9）上调，同时伴随 H3-K79 的高甲基化。因此，我们的研究证实 hDOT1L 与 Hoxa9 的错误定位在 MLLAF10 介导的白血病发生中发挥重要作用，并表明 hDOT1L 的酶活性可能为治疗干预提供潜在靶点。
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 MLLAF10-mediated leukemogenesis and suggests that the enzymatic activity of hDOT1L may provide a potential target for therapeutic intervention.