Low expression of ZFP36L2 causes glucocorticoid resistance in childhood T-cell acute lymphoblastic leukemia.
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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.