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Glucocorticoid sensitivity of T-cell lymphoblastic leukemia/lymphoma is associated with glucocorticoid receptor-mediated inhibition of Notch1 expression

Leukemia volume 27, pages 485–488 (2013)Cite this article

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To inhibit NOTCH-mediated signal transduction, we treated T-ALL cell lines with the GSI-IX (DAPT) at 5 μM, or with dimethyl sulfoxide (control vehicle). We did not observe any effects on proliferation or viability when the treatment was maintained for up to 7 days in any of the cell lines (Figure 2h only 48 h treatment is shown). Importantly, treatment with DAPT as early as 12 h led to reduced levels of activated Notch1 and Hes-1 in each of the T-ALL cell lines in which the V1744 cleaved protein could be detected, indicating that the compound effectively inhibited NOTCH1 cleavage and activation (Figure 2f time-point at 24 h is shown). Western blot analysis also demonstrated that the cell lines with activated Notch1 expressed low levels of NR3C1 (Figure 2g), reflecting the fact that aberrant activation of the NOTCH pathway could be important in glucocorticoid receptor downmodulation. However, after DAPT treatment, both Jurkat and Molt3 cell lines also expressed low levels of NR3C1, implying that glucocorticoid receptor expression is repressed in these cell lines through a mechanism other than NOTCH1/Hes-1 activation. Consistently, GSI treatment did not sensitize Jurkat and Molt3 cells to DEX treatment (Figure 2h), even though Hes-1 expression was reduced (Figure 2f). Thus, while confirming that glucocorticoid resistance of T-ALL cells requires an intact Notch signaling, we showed that glucocorticoid treatment reduces Notch1 expression specifically in glucocorticoid-sensitive T-ALL. To conclude, our data indicate that any factors that modulate NR3C1 signaling will also affect Notch1 expression and response. Thus, this mechanism could be exploited to protect cells from an excessive Notch1 response, particularly relevant in those diseases where Notch1 expression is likely to have a key role in pathogenesis.

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Acknowledgements

We thank Dr Cathrin Brisken, École Polytechnique Fédérale De Lausanne, for kindly providing the Notch1-IC retroviral construct. This work was supported by NotchIT ITN Project; FP7-MC-ITN 215761.

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  1. S Cialfi and R Palermo: These authors contributed equally to this work.

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  1. Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy

    S Cialfi, R Palermo, S Manca, S Checquolo, D Bellavia, M Pelullo, R Quaranta, A Gulino, I Screpanti & C Talora

  2. Department of Pediatrics and Infantile Neuropsychiatry, Sapienza University of Rome, Rome, Italy

    S Cialfi & C Dominici

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  1. S Cialfi
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Correspondence to I Screpanti or C Talora.

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Cialfi, S., Palermo, R., Manca, S. et al. Glucocorticoid sensitivity of T-cell lymphoblastic leukemia/lymphoma is associated with glucocorticoid receptor-mediated inhibition of Notch1 expression. Leukemia 27, 485–488 (2013). https://doi.org/10.1038/leu.2012.192

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