NEDD8-activating enzyme inhibition induces cell cycle arrest and anaphase catastrophe in malignant T-cells.

Adam S Kittai,Olga V Danilova,Tingting Liu,Guang Fan,Nur Bruss,Scott Best,Vi Lam,Alexey V Danilov

doi:10.18632/oncotarget.28063

Abstract

Peripheral T-cell lymphoma (PTCL) is characterized by poor outcomes. We and others have shown that targeting the NEDD8-activating enzyme (NAE) with an investigational inhibitor pevonedistat deregulates cell cycle and mitosis in lymphoma and leukemia. Here, we report that PTCL is characterized by increased rate of chromosomal instability. NAE inhibition promotes cell cycle arrest and induces multipolar anaphases in T-cell lymphoma cell lines, resulting in apoptosis, also observed in primary malignant PTCL cells treated with pevonedistat. We identified p27Kip1 as a mediator of anaphase catastrophe in these cells. Targeting neddylation with pevonedistat may be a promising approach to treatment of PTCL.

Highlights

Peripheral T-cell lymphoma (PTCL) is an aggressive subset of non-Hodgkin lymphomas (NHL) characterized by poor outcomes [1]
All tumors surveyed in this study (N = 14) demonstrated high level of mis-segregation using the cutoff previously established in diffuse large B-cell lymphoma (DLBCL; 31.1%) [4]
While we previously reported that lung cancer cells undergo anaphase catastrophe when exposed to chemotherapy and cyclin-dependent kinase 2 (CDK2) inhibitors [5, 6], here we show that this pathway is induced in neoplastic T-cells

Summary

Introduction

Peripheral T-cell lymphoma (PTCL) is an aggressive subset of non-Hodgkin lymphomas (NHL) characterized by poor outcomes [1]. We previously demonstrated that pharmacologic and genetic ablation of cyclin-dependent kinase 2 (CDK2) leads to an event termed anaphase catastrophe in lung cancer cells, confirmed with live-cell imaging [5,6,7]. This pathway preferentially eliminates aneuploid cancer cells by antagonizing clustering of supernumerary centrosomes during mitosis, forcing cells to undergo multipolar divisions [7]. It is not known if anaphase catastrophe occurs in NHL (PTCL) cells, and whether it may be induced by pharmacologic induction of endogenous CDK inhibitors in a cell

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Conclusion