Inhibition of histone methyltransferase EZH2 depletes leukemia stem cell of mixed lineage leukemia fusion leukemia through upregulation of p16.
Inhibition of histone methyltransferase EZH2 depletes leukemia stem cell of mixed lineage leukemia fusion leukemia through upregulation of p16.
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DOI：
10.1111/cas.12386
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发表时间：
2014-05
期刊：
影响因子：
5.7
通讯作者：
Kurokawa M
中科院分区：
文献类型：
--
作者：
Ueda K;Yoshimi A;Kagoya Y;Nishikawa S;Marquez VE;Nakagawa M;Kurokawa M
白血病干细胞（LSC）对常规化疗具有耐药性，化疗后持续存在的LSC被认为是复发的主要原因。然而，关于干细胞特性的遗传或表观遗传调控的信息仍然有限，并且几乎没有鉴定出靶向LSC的药物。表观遗传调节因子与许多细胞过程相关，包括干细胞的维持。值得注意的是polycomb组蛋白，因为它们可能控制干性，并且可以被选择性抑制剂（DZNep）靶向。因此，我们研究了EZH 2抑制在混合系白血病（MLL）融合白血病中的治疗潜力。有趣的是，通过DZNep或shRNA抑制EZH 2不仅抑制MLL融合白血病增殖，而且降低白血病起始细胞（LIC）频率。表达分析表明，p16上调负责LIC减少。p16基因的敲低取消了DZNep治疗小鼠的生存优势。染色质免疫沉淀分析表明，EZH 2在MLL/ENL和Hoxa 9/Meis 1转导的细胞中高度富集在p16的转录起始位点周围，并且H3 K27甲基化标记在MLL/ENL和Hoxa 9/Meis 1转导的细胞中高度富集，但在E2 A/HLF转导的细胞中没有。虽然Hoxa 9在MLL融合白血病中的高表达被认为是EZH 2募集的原因，但我们的数据也表明可能存在一些独立于Hoxa 9激活的其他机制来抑制p16表达，因为Hoxa 9和p16的表达水平在MLL/ENL和Hoxa 9/Meis 1转导的细胞之间并不呈负相关。总之，我们的研究结果表明，EZH 2是MLL融合白血病干细胞的潜在治疗靶点。
Leukemia stem cells (LSC) are resistant to conventional chemotherapy and persistent LSC after chemotherapy are supposed to be a major cause of relapse. However, information on genetic or epigenetic regulation of stem cell properties is still limited and LSC-targeted drugs have scarcely been identified. Epigenetic regulators are associated with many cellular processes including maintenance of stem cells. Of note are polycomb group proteins, because they potentially control stemness, and can be pharmacologically targeted by a selective inhibitor (DZNep). Therefore, we investigated the therapeutic potential of EZH2 inhibition in mixed lineage leukemia (MLL) fusion leukemia. Intriguingly, EZH2 inhibition by DZNep or shRNA not only suppressed MLL fusion leukemia proliferation but also reduced leukemia initiating cells (LIC) frequency. Expression analysis suggested that p16 upregulation was responsible for LICs reduction. Knockdown of p16 canceled the survival advantage of mice treated with DZNep. Chromatin immunoprecipitation assays demonstrated that EZH2 was highly enriched around the transcription-start-site of p16, together with H3K27 methylation marks in MLL/ENL and Hoxa9/Meis1 transduced cells but not in E2A/HLF transduced cells. Although high expression of Hoxa9 in MLL fusion leukemia is supposed to be responsible for the recruitment of EZH2, our data also suggest that there may be some other mechanisms independent of Hoxa9 activation to suppress p16 expression, because expression levels of Hoxa9 and p16 were not inversely related between MLL/ENL and Hoxa9/Meis1 transduced cells. In summary, our findings show that EZH2 is a potential therapeutic target of MLL fusion leukemia stem cells.
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影响因子：
11.2
作者：
Kotake Y;Zeng Y;Xiong Y
通讯作者：
Xiong Y
影响因子：
4.5
作者：
Kaneda A;Fujita T;Anai M;Yamamoto S;Nagae G;Morikawa M;Tsuji S;Oshima M;Miyazono K;Aburatani H
通讯作者：
Aburatani H
影响因子：
64.5
作者：
Czermin, B;Melfi, R;Pirrotta, V
通讯作者：
Pirrotta, V
影响因子：
3.5
作者：
Bhattacharyya, Joyeeta;Mihara, Keichiro;Kimura, Akiro
通讯作者：
Kimura, Akiro
DOI：
10.1007/bf03189670
发表时间：
1995-07-01
影响因子：
1.9
作者：
COULOMBE, RA;SHARMA, RP;HUGGINS, JW
通讯作者：
HUGGINS, JW