Abstract
Notch signaling deregulation is linked to the onset of several tumors including T-cell acute lymphoblastic leukemia (T-ALL). Deregulated microRNA (miRNA) expression is also associated with several cancers, including leukemias. However, the transcriptional regulators of miRNAs, as well as the relationships between Notch signaling and miRNA deregulation, are poorly understood. To identify miRNAs regulated by Notch pathway, we performed microarray-based miRNA profiling of several Notch-expressing T-ALL models. Among seven miRNAs, consistently regulated by overexpressing or silencing Notch3, we focused our attention on miR-223, whose putative promoter analysis revealed a conserved RBPjk binding site, which was nested to an NF-kB consensus. Luciferase and chromatin immunoprecipitation assays on the promoter region of miR-223 show that both Notch and NF-kB are novel coregulatory signals of miR-223 expression, being able to activate cooperatively the transcriptional activity of miR-223 promoter. Notably, the Notch-mediated activation of miR-223 represses the tumor suppressor FBXW7 in T-ALL cell lines. Moreover, we observed the inverse correlation of miR-223 and FBXW7 expression in a panel of T-ALL patient-derived xenografts. Finally, we show that miR-223 inhibition prevents T-ALL resistance to γ-secretase inhibitor (GSI) treatment, suggesting that miR-223 could be involved in GSI sensitivity and its inhibition may be exploited in target therapy protocols.
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Acknowledgements
We thank Dr Sonia Minuzzo for help in establishing T-ALL xenografts. This work was supported by the Italian Association for Cancer Research (AIRC), the Italian Ministry of University and Research (MIUR), FIRB and PRIN Programs, the European Union (FP7-MC-ITN 215761-NotchIT).
Author contributions
VK and RP designed and performed experiments, analyzed data and wrote the paper; AFC, LT, EM and GT performed experiments; SC and DB analyzed data; SI, AA, CT, EF, AG, AV and IS designed experiments, analyzed data and wrote the paper.
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Kumar, V., Palermo, R., Talora, C. et al. Notch and NF-kB signaling pathways regulate miR-223/FBXW7 axis in T-cell acute lymphoblastic leukemia. Leukemia 28, 2324–2335 (2014). https://doi.org/10.1038/leu.2014.133
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DOI: https://doi.org/10.1038/leu.2014.133
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