RNA export factor RAE1 contributes to NUP98-HOXA9-mediated leukemogenesis
RNA export factor RAE1 contributes to NUP98-HOXA9-mediated leukemogenesis
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DOI：
10.4161/cc.10.9.15494
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发表时间：
2011-05-01
期刊：
影响因子：
4.3
通讯作者：
Wong, Richard W.
中科院分区：
文献类型：
--
作者：
Funasaka, Tatsuyoshi;Nakano, Hiroshi;Wong, Richard W.
涉及核孔蛋白NUP 98蛋白的嵌合融合的染色体易位经常在急性髓性白血病（AML）中描述。所有融合蛋白具有相同的NUP 98 N末端，其含有用于与mRNA输出因子RAE 1相互作用的GLEBS基序和与转录因子HDAC 1和p300相关的FG重复。事实上，这些相互作用伴侣是否影响白血病发生尚不清楚。我们以前的研究表明RAE 1缺失导致非整倍体，这增强了肿瘤的发生。我们推测RAE 1也可能直接参与NUP 98融合介导的白血病发生。我们在这里表明，RNA干扰（RNAi）介导的NUP 98敲低导致严重的染色体分离缺陷和破坏RAE 1，但不是HDAC 1的表达和定位。接下来，我们进行了拯救实验以确认RAE 1-NUP 98复合物协调了正确的染色体分离。有趣的是，我们发现NUP 98和致白血病融合蛋白NUP 98-HOXA 9在整个细胞周期中的不同行为。引人注目的是，在NUP 98-HOXA 9转染的细胞中，RAE 1蛋白减少并错误定位。NUP 98-H 0XA 9转基因小鼠和NUP 98-H 0XA 9 AML患者进一步证实了我们的细胞解释。这些数据表明，RAE 1协调NUP 98介导的白血病发生，并提高了靶向这种负反馈回路可能为侵袭性白血病的治疗提供新策略的可能性。
Chromosomal translocations involving chimeric fusions of the nucleoporin NUP98 protein have often been described in acute myelogenous leukemia (AML). All the fusion proteins have an identical NUP98 N terminus, which contains the GLEBS motif for interaction with the mRNA export factor RAE1 and FG repeats that associate with the transcription factors HDAC1 and p300. It is virtually unknown whether these interaction partners affect leukemogenesis. We previously showed that RAE1 depletion caused aneuploidy, which enhanced tumorigenesis. We speculated that RAE1 may also be directly involved in NUP98 fusion-mediated leukemogenesis. We show here that RNA interference (RNAi)-mediated knockdown of NUP98 caused severe chromosome segregation defects and disrupted RAE1 but not HDAC1 expression and localization. Next, we performed rescue experiments to confirm that the RAE1-NUP98 complex orchestrates proper chromosome segregation. Interestingly, we found diverse behaviors of NUP98 and the leukemogenic fusion protein NUP98-HOXA9 throughout the cell cycle. Strikingly, in NUP98-HOXA9-transfected cells, RAE1 protein were reduced and mis-localized. Our cellular interpretations were further confirmed by NUP98-HOXA9 transgenic mice and the NUP98-HOXA9 AML patient. These data suggest that RAE1 orchestrates NUP98-mediated leukemogenesis and raise the possibility that targeting this negative feedback loop may provide a new strategy for the therapy of aggressive leukemias.