DOT1L inhibition blocks multiple myeloma cell proliferation by suppressing IRF4-MYC signaling.
DOT1L inhibition blocks multiple myeloma cell proliferation by suppressing IRF4-MYC signaling.
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DOI：
10.3324/haematol.2018.191262
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发表时间：
2019-01
期刊：
影响因子：
10.1
通讯作者：
Suzuki H
中科院分区：
文献类型：
--
作者：
Ishiguro K;Kitajima H;Niinuma T;Ishida T;Maruyama R;Ikeda H;Hayashi T;Sasaki H;Wakasugi H;Nishiyama K;Shindo T;Yamamoto E;Kai M;Sasaki Y;Tokino T;Nakase H;Suzuki H
表观遗传学改变在多发性骨髓瘤的发病机制中起重要作用，但其生物学和临床相关性尚未完全了解。在这里，我们表明，DOT 1 L，催化组蛋白H3赖氨酸79的甲基化，是骨髓瘤细胞生存所必需的。DOT 1 L的表达水平在单克隆丙种球蛋白病的未确定的意义和郁积型多发性骨髓瘤高于正常浆细胞。用DOT 1 L抑制剂处理诱导骨髓瘤细胞的细胞周期停滞和凋亡，并在体外强烈抑制细胞增殖。在小鼠异种移植模型中证实了DOT 1 L抑制的抗骨髓瘤作用。染色质免疫沉淀测序和微阵列分析显示，DOT 1 L抑制下调组蛋白H3赖氨酸79二甲基化和IRF 4-MYC信号转导基因在骨髓瘤细胞中的表达。此外，DOT 1 L抑制上调与免疫应答和干扰素信号传导相关的基因。具有组蛋白修饰物突变或IRF 4/MYC表达较低的骨髓瘤细胞对DOT 1 L抑制的敏感性较低，但随着治疗时间的延长，在这些细胞中实现了抗增殖作用。我们的数据表明，DOT 1 L在多发性骨髓瘤的发展中起着至关重要的作用，DOT 1 L抑制可能为骨髓瘤治疗提供新的疗法。
Epigenetic alterations play an important role in the pathogenesis in multiple myeloma, but their biological and clinical relevance is not fully understood. Here, we show that DOT1L, which catalyzes methylation of histone H3 lysine 79, is required for myeloma cell survival. DOT1L expression levels were higher in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma than in normal plasma cells. Treatment with a DOT1L inhibitor induced cell cycle arrest and apoptosis in myeloma cells, and strongly suppressed cell proliferation in vitro. The anti-myeloma effect of DOT1L inhibition was confirmed in a mouse xenograft model. Chromatin immunoprecipitation-sequencing and microarray analysis revealed that DOT1L inhibition downregulated histone H3 lysine 79 dimethylation and expression of IRF4-MYC signaling genes in myeloma cells. In addition, DOT1L inhibition upregulated genes associated with immune responses and interferon signaling. Myeloma cells with histone modifier mutations or lower IRF4/MYC expression were less sensitive to DOT1L inhibition, but with prolonged treatment, anti-proliferative effects were achieved in these cells. Our data suggest that DOT1L plays an essential role in the development of multiple myeloma and that DOT1L inhibition may provide new therapies for myeloma treatment.
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影响因子：
5.7
作者：
Hideshima T;Richardson PG;Anderson KC
通讯作者：
Anderson KC
表观遗传学在多发性骨髓瘤生物学中的作用。
影响因子：
12.8
作者：
Dimopoulos, K.;Gimsing, P.;Gronbaek, K.
通讯作者：
Gronbaek, K.
影响因子：
20.3
作者：
Martinez-Garcia, Eva;Popovic, Relja;Licht, Jonathan D.
通讯作者：
Licht, Jonathan D.
影响因子：
16.6
作者：
Ohguchi H;Hideshima T;Bhasin MK;Gorgun GT;Santo L;Cea M;Samur MK;Mimura N;Suzuki R;Tai YT;Carrasco RD;Raje N;Richardson PG;Munshi NC;Harigae H;Sanda T;Sakai J;Anderson KC
通讯作者：
Anderson KC
影响因子：
9.2
作者：
Feng, Q;Wang, HB;Zhang, Y
通讯作者：
Zhang, Y