title: DLL4 regulates NOTCH signaling and growth of T acute lymphoblastic leukemia cells in NOD/SCID mice.
abstract: Activation of the NOTCH pathway occurs commonly in T acute lymphoblastic leukemia (T-ALL) mainly due to mutations in NOTCH1 or alterations in FBW7 and is involved in the regulation of cell proliferation and survival. Since mutations hit different domains of the receptor, they are predicted to heterogeneously perturb ligand-induced NOTCH1 activity. Moreover, T-ALL cells also co-express NOTCH3 receptors which could be triggered by different ligands. In this study, we aimed to investigate the role of DLL4 in the regulation of NOTCH signaling in T-ALL cells in the context of different types of NOTCH1 mutation or wild-type NOTCH receptor, as well as the effects of DLL4 neutralization on T-ALL engraftment in mice. We found that NOTCH signaling can be stimulated in T-ALL cells in vitro by either human or murine DLL4 with heterogeneous effects, according to NOTCH1/FBW7 mutation status, and that these effects can be blocked by antibodies neutralizing DLL4, NOTCH1 or NOTCH2/3. In vivo, DLL4 is expressed in the spleen and the bone marrow (BM) of NOD/SCID mice bearing T-ALL xenografts as well as the BM of T-ALL patients. Importantly, DLL4 blockade impaired growth of T-ALL cells in NOD/SCID mice and increased leukemia cell apoptosis. These results show that DLL4 is an important component of the tumor microenvironment which contributes to the early steps of T-ALL cell growth.
authors.affiliation: Immunology and Oncology Section, Department of Surgery Oncology and Gastroenterology, University of Padova, 35100 Padova, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Minuzzo
authors.affiliation: Immunology and Oncology Section, Department of Surgery Oncology and Gastroenterology, University of Padova, 35100 Padova, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Agnusdei
authors.affiliation: Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto-IRCCS, 35100 Padova, Italy, Present addresses: Klinische Chemie und Laboratoriumsmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.
authors.forename: Irene
authors.initials: I
authors.lastname: Pusceddu
authors.affiliation: Immunology and Oncology Section, Department of Surgery Oncology and Gastroenterology, University of Padova, 35100 Padova, Italy.
authors.forename: Marica
authors.initials: M
authors.lastname: Pinazza
authors.affiliation: Immunology and Oncology Section, Department of Surgery Oncology and Gastroenterology, University of Padova, 35100 Padova, Italy, Tumor Angiogenesis Group, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Lidia
authors.initials: L
authors.lastname: Moserle
authors.affiliation: Immunology and Oncology Section, Department of Surgery Oncology and Gastroenterology, University of Padova, 35100 Padova, Italy, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, John Radcliffe Hospital, Headington, Oxford, UK and.
authors.forename: Massimo
authors.initials: M
authors.lastname: Masiero
authors.affiliation: Immunology and Oncology Section, Department of Surgery Oncology and Gastroenterology, University of Padova, 35100 Padova, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Rossi
authors.affiliation: Immunology and Oncology Section, Department of Surgery Oncology and Gastroenterology, University of Padova, 35100 Padova, Italy, Gastroenterology Section, Department of Surgery Oncology and Gastroenterology, University of Padova, Padova, Italy.
authors.forename: Marika
authors.initials: M
authors.lastname: Crescenzi
authors.affiliation: OncoMed Pharmaceuticals Inc., Redwood City, 94002 CA, USA and.
authors.forename: Timothy
authors.initials: T
authors.lastname: Hoey
authors.affiliation: Pathology Unit and Leukemia Unit, San Raffaele Scientific Institute, 20100 Milan, Italy.
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.affiliation: Immunology and Oncology Section, Department of Surgery Oncology and Gastroenterology, University of Padova, 35100 Padova, Italy, Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto-IRCCS, 35100 Padova, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Amadori
authors.affiliation: Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto-IRCCS, 35100 Padova, Italy, stefano.indraccolo@unipd.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Indraccolo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002135:Calcium-Binding Proteins; D049109:Cell Proliferation; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; C519665:DLL4 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D051880:Receptors, Notch