TRIP13 impairs mitotic checkpoint surveillance and is associated with poor prognosis in multiple myeloma.

Yi Tao,Lu Gao,Minjie Gao,Xiaosong Wu,Jumei Shi,Hongxing Yang,Hongwei Xu,Zhijian Xu,Houcai Wang,Liangning Hu,Guang Yang,Weiliang Zhu,Fenghuang Zhan,Yiwen Zhang,Dongliang Song,Bingqian Xie

doi:10.18632/oncotarget.14957

Abstract

AAA-ATPase TRIP13 is one of the chromosome instability gene recently established in multiple myeloma (MM), the second most common and incurable hematological malignancy. However, the specific function of TRIP13 in MM is largely unknown. Using sequential gene expression profiling, we demonstrated that high TRIP13 expression levels were positively correlated with progression, disease relapse, and poor prognosis in MM patients. Overexpressing human TRIP13 in myeloma cells prompted cell growth and drug resistance, and overexpressing murine TRIP13, which shares 93% sequence identity with human TRIP13, led to colony formation of NIH/3T3 fibroblasts in vitro and tumor formation in vivo. Meanwhile, the knockdown of TRIP13 inhibited myeloma cell growth, induced cell apoptosis, and reduced tumor burden in xenograft MM mice. Mechanistically, we observed that the overexpression of TRIP13 abrogated the spindle checkpoint and induced proteasome-mediated degradation of MAD2 primarily through the Akt pathway. Thus, our results demonstrate that TRIP13 may serve as a biomarker for MM disease development and prognosis, making it a potential target for future therapies.

Highlights

Multiple myeloma (MM), a clonal neoplasm characterized by the expansion of malignant plasma cells in the bone marrow, is the second most common hematological malignancy worldwide
We compared Thyroid hormone receptor-interacting protein 13 (TRIP13) expression from 51 paired MM samples obtained at baseline (BL) and at relapse (RL) using gene expression profile (GEP) in total therapy 2 (TT2) and total therapy 3 (TT3)
From another perspective, when patients in each cohort were divided into 10 equal-sized groups on the basis of the ranked expression levels of TRIP13, the proportion of patients with either MM events or death was generally positively correlated to the expression levels of TRIP13 (Figure 1D)

Summary

Introduction

Multiple myeloma (MM), a clonal neoplasm characterized by the expansion of malignant plasma cells in the bone marrow, is the second most common hematological malignancy worldwide. Spindle checkpoint proteins associated with the kinetochore will arrest the mitotic program www.impactjournals.com/oncotarget when sensing the lack of attachment and/or tension at the kinetochores, and this is part of a surveillance mechanism. These checkpoint proteins will swiftly become inactivated once all chromosomes are properly positioned. The role of spindle checkpoints is to maintain proper chromosome segregation and genetic stability by delaying metaphaseanaphase transition during cell division in the presence of defective kinetochore-microtubule attachment [4]. Dysfunctions of checkpoint proteins allow cells to go through mitosis (transition from metaphase to anaphase) prematurely, resulting in chromosomal mis-segregation and aneuploidy in cancer-prone daughter cells [3]

Methods

Results

Conclusion