Evi1 represses PTEN expression and activates PI3K/AKT/mTOR via interactions with polycomb proteins
Evi1 represses PTEN expression and activates PI3K/AKT/mTOR via interactions with polycomb proteins
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DOI：
10.1182/blood-2009-12-261602
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发表时间：
2011-03-31
期刊：
影响因子：
20.3
通讯作者：
Kurokawa, Mineo
中科院分区：
文献类型：
--
作者：
Yoshimi, Akihide;Goyama, Susumu;Kurokawa, Mineo
Evi 1（亲嗜性病毒整合位点1）是造血干细胞增殖所必需的，并与骨髓疾病的发展有关。特别是，Evi 1高表达定义了急性髓细胞白血病中最大的簇之一，并与极差的预后显著相关。然而，Evi 1介导的白血病发生的机制基础尚未完全阐明。在这里，我们表明，Evi 1直接抑制磷酸酶和张力蛋白同源物10号染色体上删除（PTEN）转录在小鼠骨髓中，这导致激活AKT/哺乳动物雷帕霉素靶（mTOR）信号。在小鼠骨髓移植模型中，Evi 1白血病对mTOR抑制剂雷帕霉素的敏感性适度增加。此外，我们发现Evi 1与几种polycomb组蛋白结合，并招募polycomb抑制复合物用于PTEN下调，这表明白血病中AKT/mTOR激活的新表观遗传机制。人类样本的表达分析和ChIP分析表明，我们在小鼠模型中的发现在人类白血病细胞中得到了重现。表达Evi 1的白血病细胞对AKT/mTOR信号的依赖性提供了抑制Evi 1致白血病活性的靶向治疗方式的第一个例子。PTEN/AKT/mTOR信号通路和Evi 1-polycomb相互作用可能是Evi 1激活的白血病有希望的治疗靶点。（血。2011;117（13）：3617-3628）
Evi1 (ecotropic viral integration site 1) is essential for proliferation of hematopoietic stem cells and implicated in the development of myeloid disorders. Particularly, high Evi1 expression defines one of the largest clusters in acute myeloid leukemia and is significantly associated with extremely poor prognosis. However, mechanistic basis of Evi1-mediated leukemogenesis has not been fully elucidated. Here, we show that Evi1 directly represses phosphatase and tensin homologue deleted on chromosome 10 (PTEN) transcription in the murine bone marrow, which leads to activation of AKT/mammalian target of rapamycin (mTOR) signaling. In a murine bone marrow transplantation model, Evi1 leukemia showed modestly increased sensitivity to an mTOR inhibitor rapamycin. Furthermore, we found that Evi1 binds to several polycomb group proteins and recruits polycomb repressive complexes for PTEN down-regulation, which shows a novel epigenetic mechanism of AKT/mTOR activation in leukemia. Expression analyses and ChIPassays with human samples indicate that our findings in mice models are recapitulated in human leukemic cells. Dependence of Evi1-expressing leukemic cells on AKT/mTOR signaling provides the first example of targeted therapeutic modalities that suppress the leukemogenic activity of Evi1. The PTEN/AKT/mTOR signaling pathway and the Evi1-polycomb interaction can be promising therapeutic targets for leukemia with activated Evi1. (Blood. 2011;117(13):3617-3628)