title: Notch signaling sustains the expression of Mcl-1 and the activity of eIF4E to promote cell survival in CLL.
abstract: 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.
authors.affiliation: Department of Experimental Medicine, Biosciences and Medical Embryology Section, University of Perugia, Perugia, Italy.
authors.forename: Filomena
authors.initials: F
authors.lastname: De Falco
authors.affiliation: Department of Experimental Medicine, Biosciences and Medical Embryology Section, University of Perugia, Perugia, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Sabatini
authors.affiliation: Department of Medicine, Hematology and Clinical Immunology Section, University of Perugia, Perugia, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Del Papa
authors.affiliation: Department of Medicine, Hematology and Clinical Immunology Section, University of Perugia, Perugia, Italy.
authors.forename: Franca
authors.initials: F
authors.lastname: Falzetti
authors.affiliation: Department of Life, Health and Environmental Sciences, Hematology Section, University of L'Aquila, L'Aquila, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Di Ianni
authors.affiliation: Department of Medicine, Hematology and Clinical Immunology Section, University of Perugia, Perugia, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Sportoletti
authors.affiliation: Department of Medicine, Hematology and Clinical Immunology Section, University of Perugia, Perugia, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Baldoni
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Screpanti
authors.affiliation: Department of Experimental Medicine, Biosciences and Medical Embryology Section, University of Perugia, Perugia, Italy.
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Marconi
authors.affiliation: Department of Experimental Medicine, Biosciences and Medical Embryology Section, University of Perugia, Perugia, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Rosati
mesh_terms: D017209:Apoptosis / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis*; D034622:RNA Interference; D034741:RNA, Small Interfering; D051881:Receptor, Notch1 / Q000235:genetics*; D051883:Receptor, Notch2 / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D039561:Eukaryotic Initiation Factor-4E; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C497761:NOTCH1 protein, human; C497764:NOTCH2 protein, human; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D051883:Receptor, Notch2
keywords: Mcl-1; Notch; cell survival; chronic lymphocytic leukemia; eIF4E