title: Notch3/Jagged1 circuitry reinforces notch signaling and sustains T-ALL.
abstract: Deregulated Notch signaling has been extensively linked to T-cell acute lymphoblastic leukemia (T-ALL). Here, we show a direct relationship between Notch3 receptor and Jagged1 ligand in human cell lines and in a mouse model of T-ALL. We provide evidence that Notch-specific ligand Jagged1 is a new Notch3 signaling target gene. This essential event justifies an aberrant Notch3/Jagged1 cis-expression inside the same cell. Moreover, we demonstrate in Notch3-IC-overexpressing T lymphoma cells that Jagged1 undergoes a raft-associated constitutive processing. The proteolytic cleavage allows the Jagged1 intracellular domain to empower Notch signaling activity and to increase the transcriptional activation of Jagged1 itself (autocrine effect). On the other hand, the release of the soluble Jagged1 extracellular domain has a positive impact on activating Notch signaling in adjacent cells (paracrine effect), finally giving rise to a Notch3/Jagged1 auto-sustaining loop that supports the survival, proliferation, and invasion of lymphoma cells and contributes to the development and progression of Notch-dependent T-ALL. These observations are also supported by a study conducted on a cohort of patients in which Jagged1 expression is associated to adverse prognosis.
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Pelullo
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Quaranta
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Talora
authors.affiliation: Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University, Latina, Italy.
authors.forename: Saula
authors.initials: S
authors.lastname: Checquolo
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: Samantha
authors.initials: S
authors.lastname: Cialfi
authors.affiliation: Department of Experimental Medicine, Sapienza University, Rome, Italy.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Felli
authors.affiliation: Department of Women's and Children's Health, University of Padova, Padova, Italy.
authors.forename: Geertruy
authors.initials: G
authors.lastname: te Kronnie
authors.affiliation: Department of Women's and Children's Health, University of Padova, Padova, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Borga
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: Zein Mersini
authors.initials: ZM
authors.lastname: Besharat
authors.affiliation: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
authors.forename: Rocco
authors.initials: R
authors.lastname: Palermo
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Di Marcotullio
authors.affiliation: Molecular Oncology Program, DeWitt Daughtry Family, Department of Surgery; Miami, FL, USA; Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Capobianco
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy; Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy; Neuromed Institute, Pozzilli, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Gulino
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy; Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy; Institute Pasteur-Foundation Cenci Bolognetti, Sapienza University, Rome, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Screpanti
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy. Electronic address: diana.bellavia@uniroma1.it.
authors.forename: Diana
authors.initials: D
authors.lastname: Bellavia
mesh_terms: D000818:Animals; D017209:Apoptosis; D002135:Calcium-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D019084:Fluorescent Antibody Technique, Indirect; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D015151:Immunoblotting; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D010957:Plasmids; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C499373:Notch3 protein, mouse; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins