title: Functional impact of NOTCH1 mutations in chronic lymphocytic leukemia.
abstract: The purpose of this study was to compare the expression and function of NOTCH1 in chronic lymphocytic leukemia (CLL) patients harboring a wild-type (WT) or mutated NOTCH1 gene. NOTCH1 mRNA and surface protein expression levels were independent of the NOTCH1 gene mutational status, consistent with the requirement for NOTCH1 signaling in this leukemia. However, compared with NOTCH1-WT CLL, mutated cases displayed biochemical and transcriptional evidence of an intense activation of the NOTCH1 pathway. In vivo, expression and activation of NOTCH1 was highest in CLL cells from the lymph nodes as confirmed by immunohistochemistry. In vitro, the NOTCH1 pathway was rapidly downregulated, suggesting that signaling relies upon micro-environmental interactions even in NOTCH1-mutated cases. Accordingly, co-culture of Jagged1(+) (the NOTCH1 ligand) nurse-like cells with autologous CLL cells sustained NOTCH1 activity over time and mediated CLL survival and resistance against pro-apoptotic stimuli, both abrogated when NOTCH1 signaling was pharmacologically switched off. Together, these results show that NOTCH1 mutations have stabilizing effects on the NOTCH1 pathway in CLL. Furthermore, micro-environmental interactions appear critical in activating the NOTCH1 pathway both in WT and mutated patients. Finally, NOTCH1 signals may create conditions that favor drug resistance, thus making NOTCH1 a potential molecular target in CLL.
authors.affiliation: Department of Medical Sciences, University of Turin, School of Medicine, Turin, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Arruga
authors.affiliation: 1] Department of Medical Sciences, University of Turin, School of Medicine, Turin, Italy [2] Department of Hematology, Dubrava University Hospital, Zagreb, Croatia.
authors.forename: B
authors.initials: B
authors.lastname: Gizdic
authors.affiliation: 1] Department of Medical Sciences, University of Turin, School of Medicine, Turin, Italy [2] Human Genetics Foundation (HuGeF), Turin, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Serra
authors.affiliation: Department of Medical Sciences, University of Turin, School of Medicine, Turin, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Vaisitti
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Ciardullo
authors.affiliation: Division of Hematology, Laboratory of Hematology Oncology, Center of Experimental Research and Medical Studies, Cittá della Salute e della Scienza University Hospital, Turin, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Coscia
authors.affiliation: Institute of Hematology, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Laurenti
authors.affiliation: Department of Onco-Hematology, IRCCS Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, Italy.
authors.forename: G
authors.initials: G
authors.lastname: D'Arena
authors.affiliation: Department of Hematology, Dubrava University Hospital, Zagreb, Croatia.
authors.forename: O
authors.initials: O
authors.lastname: Jaksic
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Center of Experimental Research and Medical Studies, University of Turin, Turin, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Inghirami
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Rossi
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Gaidano
authors.affiliation: 1] Department of Medical Sciences, University of Turin, School of Medicine, Turin, Italy [2] Human Genetics Foundation (HuGeF), Turin, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Deaglio
mesh_terms: D015536:Down-Regulation; D005434:Flow Cytometry; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D009154:Mutation; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051881:Receptor, Notch1 / Q000235:genetics*; D015398:Signal Transduction
chemical_list: C497761:NOTCH1 protein, human; D012333:RNA, Messenger; D051881:Receptor, Notch1