Author: Shi, Jumei ; Lu, Yumeng ; Chang, Shuaikang ; Zhan, Fenghuang ; Zhou, Jinfeng ; Gao, Xuejie ; Chen, Gege ; Wang, Guanli ; Feng, Qilin ; Xu, Zhijian ; Wang, Huaping ; Jia, Xinyan ; Wang, Yingcong ; Zhu, Huabin ; Yu, Dandan ; Wu, Xiaosong ; Zhang, Hui ; Zhu, Weiliang ; Yang, Guang ; Guo, Shushan ; Song, Dongliang ; Hu, Ke ; Li, Bo ; Xu, Li

Multiple myeloma stem cells (MMSCs) constitute a distinct subpopulation of tumor cells with stemness ability.Elucidating the mechanisms underlying MMSC properties is expected to shed light on the high recurrence rate and drug resistance of multiple myeloma (MM).Thyroid hormone receptor-interacting protein 13 (TRIP13) encodes a highly conserved AAA (ATPases associated with diverse cellular activities) ATP enzyme that contributes to homologous pairing, synapsis, and recombination during meiosis.This study aimed to explore the mechanisms through which TRIP13 maintains MMSC phenotype and its association with bortezomib (BTZ) resistance.To determine whether TRIP13 preserves stem cell identity in MM, we used RNA-Seq to profile transcriptomes of ARP1 cells after TRIP13 overexpression (OE).Importantly, the stemness phenotype and drug resistance induced by TRIP13 could only be reversed by GSK126 (a small mol. inhibitor targeting EZH2), while CPI-360 (an EZH1 targeted inhibitor) had no such effect.To determine the clin. value of TRIP13-EZH2 axis in MM, we examined the effect of combining DCZ0415 and GSK126 on proliferation of MM cells.The protein levels of EZH2, NANOG, SOX2, and OCT4 were analyzed by western blotting.In summary, this study revealed the key role of TRIP13 in the maintenance of MMSC characteristics.We demonstrated that aberrant TRIP13 OE promotes EZH2 deubiquitination, thereby enhancing myeloma stemness phenotype and promoting resistance to BTZ.TRIP13 OE also increases H3K27me3 recruitment to RHOB promoter region, which relies on EZH2 methyltransferase activity.Our findings provide a theor. basis for the development of clin. trials of TRIP13 inhibitors in combination with EZH2 inhibitors in patients with relapsed/refractory MM.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	-	Constellation Pharmaceuticals, Inc.	-

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