The positive feedback loop of MAD2L1/TYK2/STAT3 induces progression in B-cell acute lymphoblastic leukaemia

• Published in: Journal of cancer research and clinical oncology Vol. 149; no. 9; pp. 6527 - 6540
• Main Authors: Zhu, Liwen, Li, Xinyu, Liu, Diandian, Bai, Wenke, Yang, Huaqing, Cheng, Qianyi, Xu, Luhong, Fang, Jianpei
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.08.2023; Springer Nature B.V
• Subjects: Acute lymphoblastic leukemia; Cancer Research; Cell proliferation; Cholecystokinin; Chromatin; Feedback; Flow cytometry; Hematology; Immunoprecipitation; Internal Medicine; Leukemia; Lymphocytes B; Malignancy; Medicine; Medicine & Public Health; Oncology; Remission; Signal transduction; Stat3 protein; Therapeutic targets; Tyk2 protein; Western blotting; B-ALL; TYK2/STAT3; Proliferation; Metastasis; MAD2L1
• ISSN: 0171-5216; 1432-1335
• DOI: 10.1007/s00432-023-04613-5

Purpose 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. Methods 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. Results 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. Conclusion 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.