Department of Pathology, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, China.
Int J Mol Sci. 2023 Sep 27;24(19):14646. doi: 10.3390/ijms241914646.
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.
T 淋巴母细胞白血病（T-ALL）是一种侵袭性血液淋巴恶性肿瘤，占急性淋巴细胞白血病（ALL）的 15%。尽管通过强化化疗，其预后有所改善，但复发/难治性疾病的预后仍然较差。因此，迫切需要为 T-ALL 开发新的治疗方法。硼替佐米是一种 26S 蛋白酶体抑制剂，已被批准用于治疗浆细胞瘤和套细胞淋巴瘤。由于其良好的副作用谱，它是 ALL 治疗中研究兴趣的新型药物。尽管越来越多的 T-ALL 硼替佐米临床试验，但它在 DNA 损伤、细胞周期和有丝分裂灾难方面的详细机制研究仍难以捉摸。此外，WEE1 是一种在 ALL 中过表达并参与细胞周期调节的蛋白激酶，已被认为是许多癌症的新治疗靶点。但硼替佐米在调节 ALL 中 WEE1 表达方面的作用仍难以捉摸。在这项研究中，我们证明了硼替佐米对 T-ALL 原代样本和细胞系的治疗效果。我们的研究结果表明，硼替佐米治疗诱导 DNA 损伤并下调 WEE1，导致 DNA 受损的 G2-M 细胞周期进展。硼替佐米诱导的这种异常有丝分裂进入导致 T-ALL 中的有丝分裂灾难。总之，我们的研究结果剖析了硼替佐米的作用机制，并为使用硼替佐米治疗 T-ALL 提供了进一步的见解。我们的研究结果表明，未来使用蛋白酶体抑制剂与 DNA 损伤剂联合进行新型联合治疗的可能性，这可能填补治疗 ALL 方面的研究空白和未满足的临床需求。
