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Published on: May 10, 2017
Low expression of ZFP36L2 causes glucocorticoid resistance in childhood T-cell acute lymphoblastic leukemia
Yuening Xiang1, Mengyan Wang1, Shao Xie1
1Shanghai Key Laboratory of Birth Defects, Children's Hospital of Fudan University, National Children's Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan University.
Objective:
Glucocorticoids (GCs) are essential for the therapy of acute lymphoblastic leukemia (ALL), but glucocorticoid resistance remains a major clinical challenge, and its molecular mechanisms are not fully understood. This study aimed to investigate the role of ZFP36L2, an RNA-binding protein and potential driver gene in T-ALL, in regulating glucocorticoid sensitivity in ALL.
Methods:
ZFP36L2 expression in ALL were reanalyzed from RNA sequencing data, and the correlation between ZFP36L2 expression and clinical outcomes in ALL patients was analyzed. ZFP36L2 was knocked down in T-ALL cells to observe its effects on glucocorticoid resistance and related signaling pathways. The effect of GCs combined with γ-secretase inhibitor N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) or MEK inhibitor trametinib on drug sensitivity was detected in vitro .
Results:
ZFP36L2 expression was significantly lower in T-ALL than in B-ALL, and low ZFP36L2 expression was associated with poor early disease responses and higher relapse risk in ALL. ZFP36L2 knockdown in T-ALL cell lines significantly increased glucocorticoid resistance, weakened glucocorticoid receptor upregulation, impaired apoptosis, reduced Bcl-2 interacting mediator of cell death induction, and repressed BCL2 downregulation. Moreover, ZFP36L2 was critical for glucocorticoid-mediated suppression of the NOTCH1-HES1 and mitogen-activated protein kinase pathway. Notably, combined treatment with GCs and DAPT or trametinib enhanced drug sensitivity in vitro . Mechanistically, ZFP36L2 directly binds to the UAUUUAUU motifs in the 3' untranslated regions of BCL2, Bcl-2 interacting mediator of cell death, and NOTCH1 mRNAs, thereby regulating their stability.
Conclusion:
These findings demonstrate that ZFP36L2 is a potential regulator of glucocorticoid responsiveness in T-ALL. Combining GCs with DAPT or trametinib offers a potential therapeutic strategy for T-ALL patients, especially those with ZFP36L2 mutations or low ZFP36L2 expression.
