hDOT1L links histone methylation to leukemogenesis

被引：669

作者：

Okada, Y

Feng, Q

Lin, YH

Jiang, Q

Li, YQ

Coffield, VM

Su, LS

Xu, GL

Zhang, Y ^{[1
]}

机构：

[1] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA

[2] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA

[3] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA

来源：

CELL | 2005年 / 121卷 / 02期

关键词：

D O I：

10.1016/j.cell.2005.02.020

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：167 / 178

页数：12

共 35 条

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