Department of Pediatrics, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, 107 Yanjiang West Road, Guangzhou, 510120, Guangdong, People's Republic of China.
Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China.
J Cancer Res Clin Oncol. 2023 Aug;149(9):6527-6540. doi: 10.1007/s00432-023-04613-5. Epub 2023 Feb 13.
Mitotic arrest deficient 2 like 1 (MAD2L1) has been extensively studied in several malignancies; however, its role in B-cell acute lymphoblastic leukaemia (B-ALL) remains unclear.
The expression of MAD2L1 was evaluated by real-time quantitative polymerase chain reaction. The biological functions of MAD2L1 in B-ALL were explored through Cell Counting Kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine assay (EDU), transwell assay, flow cytometry and xenograft models. The Western blotting and co-immunoprecipitation were utilized to evaluate the interplay between MAD2L1 and the TYK2/STAT3 pathway. The luciferase reporter and chromatin immunoprecipitation (ChIP) assay were employed to identify interactions between STAT3 and MAD2L1.
We demonstrated that MAD2L1 was markedly upregulated in B-ALL, and its expression level not only correlated with the relapse and remission of the condition but also with a poor prognosis. MAD2L1 promoted the proliferation, migration and invasion of B-ALL cells in vitro and in vivo, whereas MAD2L1 knockdown had the opposite effects. Mechanistically, MAD2L1 induces the progression of B-ALL by activating the TYK2/STAT3 signaling pathway to phosphorylate. Interestingly, STAT3 induces the expression of MAD2L1 by binding directly to its promoter region, resulting in a positive-feedback loop of MAD2L1/TYK2/STAT3.
This study uncovered a reciprocal loop of MAD2L1/TYK2/STAT3, which contributed to the development of B-ALL. Therefore, MAD2L1 can be considered a potential diagnostic biomarker as well as a novel therapeutic target for B-ALL.
有丝分裂检查点缺陷蛋白 2 样 1（MAD2L1）在多种恶性肿瘤中得到了广泛研究；然而，其在 B 细胞急性淋巴细胞白血病（B-ALL）中的作用尚不清楚。
通过实时定量聚合酶链反应评估 MAD2L1 的表达。通过细胞计数试剂盒-8（CCK-8）、5-乙炔基-2'-脱氧尿苷（EDU）检测、Transwell 检测、流式细胞术和异种移植模型来探索 MAD2L1 在 B-ALL 中的生物学功能。利用 Western blot 和免疫共沉淀来评估 MAD2L1 与 TYK2/STAT3 通路之间的相互作用。利用荧光素酶报告基因和染色质免疫沉淀（ChIP）实验来鉴定 STAT3 与 MAD2L1 之间的相互作用。
我们发现 MAD2L1 在 B-ALL 中明显上调，其表达水平不仅与疾病的复发和缓解相关，还与预后不良相关。MAD2L1 在体外和体内促进了 B-ALL 细胞的增殖、迁移和侵袭，而 MAD2L1 敲低则产生相反的效果。从机制上讲，MAD2L1 通过激活 TYK2/STAT3 信号通路来磷酸化，从而诱导 B-ALL 的进展。有趣的是，STAT3 通过直接结合其启动子区域诱导 MAD2L1 的表达，从而形成 MAD2L1/TYK2/STAT3 的正反馈环。
本研究揭示了 MAD2L1/TYK2/STAT3 的相互反馈回路，这有助于 B-ALL 的发展。因此，MAD2L1 可以被视为 B-ALL 的潜在诊断生物标志物和新型治疗靶点。
