The AAA+ ATPase RUVBL2 is a critical mediator of MLL-AF9 oncogenesis
The AAA+ ATPase RUVBL2 is a critical mediator of MLL-AF9 oncogenesis
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DOI：
10.1038/leu.2013.42
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发表时间：
2013-07-01
期刊：
影响因子：
11.4
通讯作者：
Williams, O.
中科院分区：
文献类型：
--
作者：
Osaki, H.;Walf-Vorderwuebecke, V.;Williams, O.
儿童急性髓性白血病中最常见的染色体易位影响11 q23位点，并产生混合谱系白血病（MLL）融合基因，MLL-AF 9是最常见的。MLL-AF 9融合基因已显示在小鼠和人类模型中诱导白血病。在这项研究中，我们证明MLL-AF 9的致白血病活性需要RUVBL 2（RuvB样2），这是一种AAA+ ATP酶家族成员，在广泛的细胞过程中发挥作用，包括染色质重塑和转录调控。RUVBL 2的表达依赖于MLL-AF 9，因为它在用融合基因使人脐带血来源的造血祖细胞永生化后增加，并且在条件永生化小鼠细胞中融合基因表达丧失后降低。短发夹RNA介导的沉默实验表明，永生化的人细胞和MLL-AF 9表达的人白血病细胞系THP-1都需要RUVBL 2表达来增殖和存活。此外，抑制THP-1细胞中RUVBL 2的表达导致端粒酶活性和克隆形成潜力降低。这些数据用显性阴性步行者B突变的RUVBL 2构建体证实。总之，这些数据表明靶向RUVBL 2作为MLL-AF 9相关白血病的潜在治疗策略的可能性。
The most frequent chromosomal translocations in pediatric acute myeloid leukemia affect the 11q23 locus and give rise to mixed lineage leukemia (MLL) fusion genes, MLL-AF9 being the most prevalent. The MLL-AF9 fusion gene has been shown to induce leukemia in both mouse and human models. In this study, we demonstrate that leukemogenic activity of MLL-AF9 requires RUVBL2 (RuvB-like 2), an AAA+ ATPase family member that functions in a wide range of cellular processes, including chromatin remodeling and transcriptional regulation. Expression of RUVBL2 was dependent on MLL-AF9, as it increased upon immortalization of human cord blood-derived hematopoietic progenitor cells with the fusion gene and decreased following loss of fusion gene expression in conditionally immortalized mouse cells. Short hairpin RNA-mediated silencing experiments demonstrated that both the immortalized human cells and the MLL-AF9-expressing human leukemia cell line THP-1 required RUVBL2 expression for proliferation and survival. Furthermore, inhibition of RUVBL2 expression in THP-1 cells led to reduced telomerase activity and clonogenic potential. These data were confirmed with a dominant-negative Walker B-mutated RUVBL2 construct. Taken together, these data suggest the possibility of targeting RUVBL2 as a potential therapeutic strategy for MLL-AF9-associated leukemia.