Inhibition of Proteasomal Deubiquitinases USP14 and UCHL5 Overcomes Tyrosine Kinase Inhibitor Resistance in Chronic Myeloid Leukaemia

Overview

Journal Clin Transl Med

Publisher Wiley

Specialty General Medicine

Date 2022 Sep 9

PMID 36082692

Authors

Liling Jiang

Qingyan He

Xin Chen

Aochu Liu

Wa Ding

Haichuan Zhang

Xinmei Chen

Huan Zhou

Yi Meng

Bingyuan Liu

Guanjie Peng

Chunyan Wang

Jinbao Liu

Xianping Shi

Affiliations

Soon will be listed here.

Abstract

Background: Chronic myeloid leukaemia (CML) is a haematological cancer featured by the presence of BCR-ABL fusion protein with abnormal tyrosine kinase activation. Classical tyrosine kinase inhibitor (TKI)-based therapies are available to patients with CML. However, acquired resistance to TKI has been a challenging obstacle, especially stubborn T315I mutation is the most common cause. Therefore, it is especially urgent to find more effective targets to overcome TKI resistance induced by BCR-ABL . Proteasomal deubiquitinases (USP14 and UCHL5) have fundamental roles in the ubiquitin-proteasome system and possess multiple functions during cancer progression.

Methods: The human peripheral blood mononuclear cells were collected to measure the mRNA expression of USP14 and UCHL5, as well as to detect the toxicity effect of b-AP15. We explored the effect of b-AP15 on the activity of proteasomal deubiquitinases. We detected the effects of b-AP15 on BCR-ABL and BCR-ABL CML cells in vitro and in the subcutaneous tumour model. We knocked down USP14 and/or UCHL5 by shRNA to explore whether these proteasomal deubiquitinases are required for cell proliferation of CML.

Results: In this study, we found that increased expression of the proteasomal deubiquitinase USP14 and UCHL5 in primary cancer cells from CML patients compared to healthy donors. b-AP15, an inhibitor of USP14 and UCHL5, exhibited potent tumour-killing activity in BCR-ABL and BCR-ABL CML cell lines, as well as in CML xenografts and primary CML cells. Mechanically, pharmacological or genetic inhibition of USP14 and UCHL5 induced cell apoptosis and decreased the protein level of BCR-ABL in CML cells expressing BCR-ABL and BCR-ABL . Moreover, b-AP15 synergistically enhanced the cytotoxic effect caused by TKI imatinib in BCR-ABL and BCR-ABL CML cells.

Conclusion: Collectively, our results demonstrate targeting USP14 and UCHL5 as a potential strategy for combating TKI resistance in CML.

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Inhibition of proteasomal deubiquitinases USP14 and UCHL5 overcomes tyrosine kinase inhibitor resistance in chronic myeloid leukaemia.

Jiang L, He Q, Chen X, Liu A, Ding W, Zhang H Clin Transl Med. 2022; 12(9):e1038.

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