The NEDD8-activating enzyme inhibitor MLN4924 induces G2 arrest and apoptosis in T-cell acute lymphoblastic leukemia
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- 英文论文题名：The NEDD8-activating enzyme inhibitor MLN4924 induces G2 arrest and apoptosis in T-cell acute lymphoblastic leukemia
- 论文作者：Han Kun ; Qingyang Wang ; Jiyan Zhang
- 英文论文作者：Han Kun ; Qingyang Wang ; Jiyan Zhang ; Beijing Institute of Basic Medical Sciences
- 年：2016
- 作者机构：Beijing Institute of Basic Medical Sciences;
- 英文论文关键词：G2 arrest ; MLN4924 ; T-ALL ; apoptosis ; neddylation
- 会议召开时间：2016-11-04
- 会议录名称：第十一届全国免疫学学术大会摘要汇编
- 英文会议录名称：Abstracts of 2016 CSI Congress on Immunology
- 语种：英文
- 分类号：R733.71
- 学会代码：IGMD
- 会议名称：第十一届全国免疫学学术大会
- 会议地点：中国安徽合肥
- 主办单位：中国免疫学会
- 学会名称：中国免疫学会
- 页数：1
- 文件大小：1291k
- 原文格式：D
- 会议级别：全国
摘要
Target: The first-in-class compound MLN4924 is a small molecule inhibitor that selectively inactivates NEDD8-activating enzyme(NAE). The anticancer effects of MLN4924 have been attributed to impaired neddylation of Cullin proteins. Here, we would like to invest whether MLN4924 has an anti-blood-tumor effect. Methods: We show that treatment of T-cell acute lymphoblastic leukemia(T-ALL) cells with MLN4924 potently suppressed the neddylation of Cullins and the oncogenic growth of T-ALL cells in-vitro. Moreover, MLN4924 induced disease regression in an in vivo xenograft model. MLN4924 also induced cell cycle arrest at G2 phase and apoptosis in T-ALL cells. However, inhibition of the neddylation of Cullins alone could not explain the effects of MLN4924 in T-ALL cells. Gene expression profiling indicated ribosome function, steroid biosynthesis, and hematopoietic cell lineage pathways were affected by MLN4924 treatment. MLN4924 also induced nucleolar disruption, suggesting nucleolar stress signaling might contribute to the anticancer effects of MLN4924 in T-ALL cells. In addition, MLN4924 treatment reduced 14-3-3ξ\δ protein levels in T-ALL cells. Results: MLN4924 treatment can lead to in vitro cell cycle arrest, cell apoptosis, T-ALL cell nucleolar disruption and in vivo decrease of xenograts volume, number and weight.Conclusions: MLN4924 may inhibit T-ALL cell proliferation via several pathways and thus has the anticancer effects against T-ALL.
Target: The first-in-class compound MLN4924 is a small molecule inhibitor that selectively inactivates NEDD8-activating enzyme(NAE). The anticancer effects of MLN4924 have been attributed to impaired neddylation of Cullin proteins. Here, we would like to invest whether MLN4924 has an anti-blood-tumor effect. Methods: We show that treatment of T-cell acute lymphoblastic leukemia(T-ALL) cells with MLN4924 potently suppressed the neddylation of Cullins and the oncogenic growth of T-ALL cells in-vitro. Moreover, MLN4924 induced disease regression in an in vivo xenograft model. MLN4924 also induced cell cycle arrest at G2 phase and apoptosis in T-ALL cells. However, inhibition of the neddylation of Cullins alone could not explain the effects of MLN4924 in T-ALL cells. Gene expression profiling indicated ribosome function, steroid biosynthesis, and hematopoietic cell lineage pathways were affected by MLN4924 treatment. MLN4924 also induced nucleolar disruption, suggesting nucleolar stress signaling might contribute to the anticancer effects of MLN4924 in T-ALL cells. In addition, MLN4924 treatment reduced 14-3-3ξ\δ protein levels in T-ALL cells. Results: MLN4924 treatment can lead to in vitro cell cycle arrest, cell apoptosis, T-ALL cell nucleolar disruption and in vivo decrease of xenograts volume, number and weight.Conclusions: MLN4924 may inhibit T-ALL cell proliferation via several pathways and thus has the anticancer effects against T-ALL.
Target: The first-in-class compound MLN4924 is a small molecule inhibitor that selectively inactivates NEDD8-activating enzyme(NAE). The anticancer effects of MLN4924 have been attributed to impaired neddylation of Cullin proteins. Here, we would like to invest whether MLN4924 has an anti-blood-tumor effect. Methods: We show that treatment of T-cell acute lymphoblastic leukemia(T-ALL) cells with MLN4924 potently suppressed the neddylation of Cullins and the oncogenic growth of T-ALL cells in-vitro. Moreover, MLN4924 induced disease regression in an in vivo xenograft model. MLN4924 also induced cell cycle arrest at G2 phase and apoptosis in T-ALL cells. However, inhibition of the neddylation of Cullins alone could not explain the effects of MLN4924 in T-ALL cells. Gene expression profiling indicated ribosome function, steroid biosynthesis, and hematopoietic cell lineage pathways were affected by MLN4924 treatment. MLN4924 also induced nucleolar disruption, suggesting nucleolar stress signaling might contribute to the anticancer effects of MLN4924 in T-ALL cells. In addition, MLN4924 treatment reduced 14-3-3ξ\δ protein levels in T-ALL cells. Results: MLN4924 treatment can lead to in vitro cell cycle arrest, cell apoptosis, T-ALL cell nucleolar disruption and in vivo decrease of xenograts volume, number and weight.Conclusions: MLN4924 may inhibit T-ALL cell proliferation via several pathways and thus has the anticancer effects against T-ALL.
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