MLL 重排白血病依赖 DOT1L 导致的异常 H3K79 甲基化。
MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L.
机构信息
Division of Hematology/Oncology, Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
出版信息
Cancer Cell. 2011 Jul 12;20(1):66-78. doi: 10.1016/j.ccr.2011.06.010.
Abstract
The histone 3 lysine 79 (H3K79) methyltransferase Dot1l has been implicated in the development of leukemias bearing translocations of the Mixed Lineage Leukemia (MLL) gene. We identified the MLL-fusion targets in an MLL-AF9 leukemia model, and conducted epigenetic profiling for H3K79me2, H3K4me3, H3K27me3, and H3K36me3 in hematopoietic progenitor and leukemia stem cells (LSCs). We found abnormal profiles only for H3K79me2 on MLL-AF9 fusion target loci in LSCs. Inactivation of Dot1l led to downregulation of direct MLL-AF9 targets and an MLL translocation-associated gene expression signature, whereas global gene expression remained largely unaffected. Suppression of MLL translocation-associated gene expression corresponded with dependence of MLL-AF9 leukemia on Dot1l in vivo. These data point to DOT1L as a potential therapeutic target in MLL-rearranged leukemia.
摘要
组蛋白 3 赖氨酸 79（H3K79）甲基转移酶 Dot1l 与携带混合谱系白血病（MLL）基因易位的白血病的发生有关。我们在 MLL-AF9 白血病模型中鉴定了 MLL 融合靶标，并对造血祖细胞和白血病干细胞（LSCs）中的 H3K79me2、H3K4me3、H3K27me3 和 H3K36me3 进行了表观遗传学分析。我们发现仅在 LSCs 中的 MLL-AF9 融合靶标位点上存在 H3K79me2 的异常谱。Dot1l 的失活导致直接的 MLL-AF9 靶基因的下调和与 MLL 易位相关的基因表达特征，而全局基因表达基本上没有受到影响。MLL 易位相关基因表达的抑制与体内 MLL-AF9 白血病对 Dot1l 的依赖性相对应。这些数据表明 DOT1L 可能是 MLL 重排白血病的潜在治疗靶点。
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本文引用的文献
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Blood. 2011 Jun 23;117(25):6912-22. doi: 10.1182/blood-2011-02-334359. Epub 2011 Apr 26.
2
Requirement for Dot1l in murine postnatal hematopoiesis and leukemogenesis by MLL translocation.Dot1l 在 MLL 易位诱导的小鼠出生后造血和白血病发生中的作用。
Blood. 2011 May 5;117(18):4759-68. doi: 10.1182/blood-2010-12-327668. Epub 2011 Feb 25.
3
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Cancer Res. 2010 Dec 15;70(24):10234-42. doi: 10.1158/0008-5472.CAN-10-3294.
4
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5
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6
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7
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