The NEDD8-activating enzyme inhibitor MLN4924 induces G2 arrest and apoptosis in T-cell acute lymphoblastic leukemia.

Kun Han,Qingyang Wang,Huanling Cao,Guihua Qiu,Beifen Shen,Junxia Cao,Xin Li,Jing Wang,Jiyan Zhang

doi:10.18632/oncotarget.8068

Abstract

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.

Highlights

T-cell acute lymphoblastic leukemia (T-ALL) arises due to multiple genetic mutations in immature T cells that block differentiation, enhance survival, and lead to proliferation of malignant clones [1, 2]
MLN4924 dose-dependently reduces the neddylation of Cullins in T-ALL cells
Our work suggests that MLN4924 might be effective in treating T-ALL

Summary

Introduction

T-cell acute lymphoblastic leukemia (T-ALL) arises due to multiple genetic mutations in immature T cells that block differentiation, enhance survival, and lead to proliferation of malignant clones [1, 2]. Intensified chemotherapy and bone marrow transplantation have improved survival rates, the 20% of T-ALL patients who relapse have little to no chance of a cure [1, 2]. A better understanding of oncogenic signaling pathways in T-ALL might improve treatments for such patients. NEDD8 (neural precursor cell expressed developmentally downregulated protein 8) is the ubiquitinlike protein most homologous to ubiquitin [3, 4]. The most well-characterized substrates of neddylation are the Cullin proteins, which are essential components of Skp1/Cullin/F-box protein (SCF)-like ubiquitin ligase complexes and play a pivotal role in ubiquitin-mediated proteolysis [5, 6]. SCF activity, which controls cell cycle progression, requires the neddylation of Cullins. Neddylation dysfunctions have been implicated in neurodegenerative diseases and cancer [3, 4]

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