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

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

doi:10.18632/oncotarget.28063

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Research Papers:

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

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

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Oncotarget. 2021; 12:2068-2074. https://doi.org/10.18632/oncotarget.28063

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Abstract

Adam S. Kittai1^,*, Olga V. Danilova2^,*, Vi Lam2, Tingting Liu2, Nur Bruss3, Scott Best3, Guang Fan3 and Alexey V. Danilov2

1 The Ohio State University, Columbus, OH 43210, USA

2 City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA

3 Oregon Health and Science University, Portland, OR 97239, USA

* These authors contributed equally to this work

Correspondence to:

Alexey V. Danilov,

email:

[email protected]

Keywords: pevonedistat; T-cell lymphoma; chromosomal instability; anaphase catastrophe

Received: June 26, 2021 Accepted: August 18, 2021 Published: September 28, 2021

Copyright: © 2021 Kittai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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 p27^Kip1 as a mediator of anaphase catastrophe in these cells. Targeting neddylation with pevonedistat may be a promising approach to treatment of PTCL.

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Research Papers:

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

Abstract