Leukemic transformation by the MLL-AF6 fusion oncogene requires the H3K79 methyltransferase Dot1l
Leukemic transformation by the MLL-AF6 fusion oncogene requires the H3K79 methyltransferase Dot1l
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DOI：
10.1182/blood-2012-11-465120
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发表时间：
2013-03-28
期刊：
影响因子：
20.3
通讯作者：
Armstrong, Scott A.
中科院分区：
文献类型：
--
作者：
Deshpande, Aniruddha J.;Chen, Liying;Armstrong, Scott A.
t（6; 11）（q27; q23）是一种编码MLLAF 6融合癌蛋白的复发性染色体重排，在多种血液恶性肿瘤患者中观察到。t（6;11）（q27;q23）的存在与AML患者的总生存期较差有关。在这项研究中，我们证明MLL-AF 6需要组蛋白甲基转移酶DOT 1 L的持续活性来维持MLL-AF 6驱动的致癌基因表达程序的表达。利用基因表达分析和全基因组染色质免疫沉淀研究，然后进行下一代测序，我们发现在小鼠MLL-AF 6白血病以及携带t（6;11）（q27;q23）易位的人骨髓单核细胞白血病细胞系ML 2中，ML融合靶基因在赖氨酸79（H3 K79）二甲基化处显示出显著高水平的组蛋白3。使用条件性敲除小鼠模型靶向破坏Dot 1 l抑制MLL-AF 6融合癌基因介导的白血病发生。此外，鼠MLL-AF 6转化细胞以及人MLL-AF 6阳性ML 2白血病细胞系均显示出对EPZ 0004777的特异性敏感性，EPZ 0004777是一种最近描述的Dot 1 l的选择性小分子抑制剂。Dot 1 l抑制导致MLL-AF 6转化细胞的增殖显著降低、MLL-AF 6靶基因表达降低和细胞周期停滞。这些结果表明，携带t（6;11）（q27;q23）易位的患者可能受益于靶向异常H3 K79甲基化的治疗剂。
The t(6;11)(q27;q23) is a recurrent chromosomal rearrangement that encodes the MLLAF6 fusion oncoprotein and is observed in patients with diverse hematologic malignancies. The presence of the t(6;11)(q27;q23) has been linked to poor overall survival in patients with AML. In this study, we demonstrate that MLL-AF6 requires continued activity of the histone-methyltransferase DOT1L to maintain expression of the MLL-AF6-driven oncogenic gene-expression program. Using gene-expression analysis and genome-wide chromatin immunoprecipitation studies followed by next generation sequencing, we found that MLL-fusion target genes display markedly high levels of histone 3 at lysine 79 (H3K79) dimethylation in murine MLL-AF6 leukemias as well as in ML2, a human myelomonocytic leukemia cell line bearing the t(6;11)(q27;q23) translocation. Targeted disruption of Dot1l using a conditional knockout mouse model inhibited leukemogenesis mediated by the MLL-AF6 fusion oncogene. Moreover, both murine MLL-AF6-transformed cells as well as the human MLL-AF6-positive ML2 leukemia cell line displayed specific sensitivity to EPZ0004777, a recently described, selective, small-molecule inhibitor of Dot1l. Dot1l inhibition resulted in significantly decreased proliferation, decreased expression of MLL-AF6 target genes, and cell cycle arrest of MLL-AF6-transformed cells. These results indicate that patients bearing the t(6;11)(q27;q23) translocation may benefit from therapeutic agents targeting aberrant H3K79 methylation.