The NEDD8-activating enzyme inhibitor MLN4924 induces G2 arrest and apoptosis in T-cell acute lymphoblastic leukemia
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Kun Han1, Qingyang Wang1, Huanling Cao1, Guihua Qiu1, Junxia Cao1, Xin Li1, Jing Wang1, Beifen Shen1, Jiyan Zhang1
1Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing 100850, P. R. China
Jiyan Zhang, e-mail: firstname.lastname@example.org
Keywords: neddylation, MLN4924, T-ALL, G2 arrest, apoptosis
Received: August 24, 2015 Accepted: February 29, 2016 Published: March 14, 2016
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 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. Thus, MLN4924 may inhibit T-ALL cell proliferation via several pathways.
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