Histone H3 lysine 79 methyltransferase Dot1 is required for immortalization by MLL oncogenes.
Histone H3 lysine 79 methyltransferase Dot1 is required for immortalization by MLL oncogenes.
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DOI：
10.1158/0008-5472.can-10-3294
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发表时间：
2010-12-15
期刊：
影响因子：
11.2
通讯作者：
Zhang W
中科院分区：
文献类型：
--
作者：
Chang MJ;Wu H;Achille NJ;Reisenauer MR;Chou CW;Zeleznik-Le NJ;Hemenway CS;Zhang W
由MLL与多种配对蛋白融合而产生的嵌合癌蛋白可引起生物学上独特的临床侵袭性急性白血病。然而，mll介导的白血病转化机制尚不完全清楚。Dot1是唯一已知的组蛋白H3赖氨酸79 （H3K79）甲基转移酶，已被证明与多个MLL融合伙伴相互作用，包括AF9、ENL、AF10和AF17。在这项研究中，我们利用条件Dot1缺失模型来研究Dot1在MLL融合蛋白介导的造血祖细胞永生化中的作用。Western blot和质谱分析显示，dot1缺失的细胞缺少H3K79甲基化标记。我们发现Dot1活性的丧失降低了MLL癌蛋白而不是白血病癌蛋白E2a-Pbx1永生化细胞的细胞活力和集落形成潜力。虽然这种作用在MLL- af9中最为明显，但我们发现Dot1有助于其他MLL癌蛋白永生细胞的活力，而这些MLL癌蛋白并不直接招募Dot1。通过MLL融合永生化的细胞也显示出增加的凋亡，这表明Dot1参与了存活途径。总之，我们的数据表明，在MLL融合蛋白介导的白血病发生中，Dot1是一个关键的需求，并暗示Dot1是一个潜在的治疗靶点。
Chimeric oncoproteins resulting from fusion of MLL to a wide variety of partnering proteins cause biologically distinctive and clinically aggressive acute leukemias. However, the mechanism of MLL-mediated leukemic transformation is not fully understood. Dot1, the only known histone H3 lysine 79 (H3K79) methyltransferase, has been shown to interact with multiple MLL fusion partners including AF9, ENL, AF10, and AF17. In this study, we utilize a conditional Dot1l deletion model to investigate the role of Dot1 in hematopoietic progenitor cell immortalization by MLL fusion proteins. Western blot and mass spectrometry show that Dot1-deficient cells are depleted of the global H3K79 methylation mark. We find that loss of Dot1 activity attenuates cell viability and colony formation potential of cells immortalized by MLL oncoproteins but not by the leukemic oncoprotein E2a-Pbx1. Although this effect is most pronounced for MLL-AF9, we find that Dot1 contributes to the viability of cells immortalized by other MLL oncoproteins that are not known to directly recruit Dot1. Cells immortalized by MLL fusions also show increased apoptosis, suggesting the involvement of Dot1 in survival pathways. In summary, our data point to a pivotal requirement for Dot1 in MLL fusion protein–mediated leukemogenesis and implicate Dot1 as a potential therapeutic target.