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