Notch signaling sustains the expression of Mcl-1 and the activity of eIF4E to promote cell survival in CLL
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Filomena De Falco1, Rita Sabatini1, Beatrice Del Papa2, Franca Falzetti2, Mauro Di Ianni3, Paolo Sportoletti2, Stefano Baldoni2, Isabella Screpanti4, Pierfrancesco Marconi1 and Emanuela Rosati1
1 Department of Experimental Medicine, Biosciences and Medical Embryology Section, University of Perugia, Perugia, Italy
2 Department of Medicine, Hematology and Clinical Immunology Section, University of Perugia, Perugia, Italy
3 Department of Life, Health and Environmental Sciences, Hematology Section, University of L’Aquila, L’Aquila, Italy
4 Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
Emanuela Rosati, email:
Keywords: chronic lymphocytic leukemia, Notch, Mcl-1, eIF4E, cell survival
Received: February 20, 2015 Accepted: April 23, 2015 Published: May 12, 2015
In chronic lymphocytic leukemia (CLL), Notch1 and Notch2 signaling is constitutively activated and contributes to apoptosis resistance. We show that genetic inhibition of either Notch1 or Notch2, through small-interfering RNA, increases apoptosis of CLL cells and is associated with decreased levels of the anti-apoptotic protein Mcl-1. Thus, Notch signaling promotes CLL cell survival at least in part by sustaining Mcl-1 expression. In CLL cells, an enhanced Notch activation also contributes to the increase in Mcl-1 expression and cell survival induced by IL-4.
Mcl-1 downregulation by Notch targeting is not due to reduced transcription or degradation by caspases, but in part, to increased degradation by the proteasome. Mcl-1 downregulation by Notch targeting is also accompanied by reduced phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), suggesting that this protein is another target of Notch signaling in CLL cells.
Overall, we show that Notch signaling sustains CLL cell survival by promoting Mcl-1 expression and eIF4E activity, and given the oncogenic role of these factors, we underscore the therapeutic potential of Notch inhibition in CLL.
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