1. Academic Validation
  2. Bortezomib Is Effective in the Treatment of T Lymphoblastic Leukaemia by Inducing DNA Damage, WEE1 Downregulation, and Mitotic Catastrophe

Bortezomib Is Effective in the Treatment of T Lymphoblastic Leukaemia by Inducing DNA Damage, WEE1 Downregulation, and Mitotic Catastrophe

  • Int J Mol Sci. 2023 Sep 27;24(19):14646. doi: 10.3390/ijms241914646.
Rahman Ud Din 1 Anan Jiao 1 Yinxia Qiu 1 Aarmann Anil Mohinani Mohan 1 Kei-Ching Yuen 1 Hoi-Tung Wong 1 Timothy Ming-Hun Wan 1 Phoebe On-Yi Wong 1 Chun-Fung Sin 1
Affiliations

Affiliation

  • 1 Department of Pathology, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, China.
Abstract

T lymphoblastic leukemia (T-ALL) is an aggressive haematolymphoid malignancy comprising 15% of acute lymphoblastic leukemia (ALL). Although its prognosis has improved with intensive chemotherapy, the relapse/refractory disease still carries a dismal prognosis. Thus, there is an urgent need to develop novel therapy for T-ALL. Bortezomib, a 26S Proteasome Inhibitor, is licensed to treat plasma cell myeloma and mantle cell lymphoma. Due to its favorable side effect profile, it is a novel agent of research interest in the treatment of ALL. Despite an increasing number of clinical trials of bortezomib in T-ALL, its detailed mechanistic study in terms of DNA damage, cell cycle, and mitotic catastrophe remains elusive. Moreover, Wee1, a protein kinase overexpressed in ALL and involved in cell-cycle regulation, has been known to be a novel therapeutic target in many cancers. But the role of bortezomib in modulating Wee1 expression in ALL still remains elusive. In this study, we demonstrate the therapeutic efficacy of bortezomib on T-ALL primary samples and cell lines. Our findings reveal that bortezomib treatment induces DNA damage and downregulates Wee1, leading to G2-M cell-cycle progression with damaged DNA. This abnormal mitotic entry induced by bortezomib leads to mitotic catastrophe in T-ALL. In conclusion, our findings dissect the mechanism of action of bortezomib and provide further insights into the use of bortezomib to treat T-ALL. Our findings suggest the possibility of novel combination therapy using Proteasome inhibitors together with DNA-damaging agents in the future, which may fill the research gaps and unmet clinical needs in treating ALL.

Keywords

DNA damage; WEE1; acute lymphoblastic leukemia; bortezomib; mitotic catastrophe; proteasome inhibitors.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-10993
    99.97%, Wee1抑制剂