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- Title
The positive feedback loop of MAD2L1/TYK2/STAT3 induces progression in B-cell acute lymphoblastic leukaemia.
- Authors
Zhu, Liwen; Li, Xinyu; Liu, Diandian; Bai, Wenke; Yang, Huaqing; Cheng, Qianyi; Xu, Luhong; Fang, Jianpei
- Abstract
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.
- Subjects
LYMPHOBLASTIC leukemia; ACUTE leukemia; POLYMERASE chain reaction; PROMOTERS (Genetics); WESTERN immunoblotting
- Publication
Journal of Cancer Research & Clinical Oncology, 2023, Vol 149, Issue 9, p6527
- ISSN
0171-5216
- Publication type
Article
- DOI
10.1007/s00432-023-04613-5