title: The enzymatic activities of CD38 enhance CLL growth and trafficking: implications for therapeutic targeting.
abstract: The ecto-enzyme CD38 is gaining momentum as a novel therapeutic target for patients with hematological malignancies, with several anti-CD38 monoclonal antibodies in clinical trials with promising results. In chronic lymphocytic leukemia (CLL) CD38 is a marker of unfavorable prognosis and a central factor in the pathogenetic network underlying the disease: activation of CD38 regulates genetic pathways involved in proliferation and movement. Here we show that CD38 is enzymatically active in primary CLL cells and that its forced expression increases disease aggressiveness in a xenograft model. The effect is completely lost when using an enzyme-deficient version of CD38 with a single amino-acid mutation. Through the enzymatic conversion of NAD into ADPR (ADP-ribose) and cADPR (cyclic ADP-ribose), CD38 increases cytoplasmic Ca(2+) concentrations, positively influencing proliferation and signaling mediated via chemokine receptors or integrins. Consistently, inhibition of the enzymatic activities of CD38 using the flavonoid kuromanin blocks CLL chemotaxis, adhesion and in vivo homing. In a short-term xenograft model using primary cells, kuromanin treatment traps CLL cells in the blood, thereby increasing responses to chemotherapy. These results suggest that monoclonal antibodies that block the enzymatic activities of CD38 or enzyme inhibitors may prove therapeutically useful.
authors.affiliation: 1] Department of Medical Sciences, School of Medicine and Human Genetics Foundation, University of Torino, Torino, Italy [2] Human Genetics Foundation (HuGeF), Torino, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Vaisitti
authors.affiliation: 1] Department of Medical Sciences, School of Medicine and Human Genetics Foundation, University of Torino, Torino, Italy [2] Human Genetics Foundation (HuGeF), Torino, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Audrito
authors.affiliation: 1] Department of Medical Sciences, School of Medicine and Human Genetics Foundation, University of Torino, Torino, Italy [2] Human Genetics Foundation (HuGeF), Torino, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Serra
authors.affiliation: 1] Department of Medical Sciences, School of Medicine and Human Genetics Foundation, University of Torino, Torino, Italy [2] Human Genetics Foundation (HuGeF), Torino, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Buonincontri
authors.affiliation: DIMES-Section of Biochemistry AND CEBR, University of Genova, Genova, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Sociali
authors.affiliation: DIMES-Section of Biochemistry AND CEBR, University of Genova, Genova, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Mannino
authors.affiliation: Human Genetics Foundation (HuGeF), Torino, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Pagnani
authors.affiliation: Centro di Riferimento Oncologico (CRO) IRCCS, Aviano, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Zucchetto
authors.affiliation: Centro di Riferimento Oncologico (CRO) IRCCS, Aviano, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Tissino
authors.affiliation: Division of Hematology, University of Torino, Azienda Universitaria Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Vitale
authors.affiliation: Division of Hematology, University of Torino, Azienda Universitaria Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Coscia
authors.affiliation: Institute of Biophysics, CNR, Genova, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Usai
authors.affiliation: Institute of Cancer & Genetics, Cardiff University, Heath Park, Cardiff, UK.
authors.forename: C
authors.initials: C
authors.lastname: Pepper
authors.affiliation: Centro di Riferimento Oncologico (CRO) IRCCS, Aviano, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Gattei
authors.affiliation: DIMES-Section of Biochemistry AND CEBR, University of Genova, Genova, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Bruzzone
authors.affiliation: 1] Department of Medical Sciences, School of Medicine and Human Genetics Foundation, University of Torino, Torino, Italy [2] Human Genetics Foundation (HuGeF), Torino, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Deaglio
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D000872:Anthocyanins / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D002633:Chemotaxis; D005419:Flavonoids / Q000494:pharmacology; D020869:Gene Expression Profiling; D005960:Glucosides / Q000494:pharmacology; D006801:Humans; D016023:Integrins / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000628:therapy*; D008297:Male; D021962:Membrane Microdomains; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009154:Mutation; D009368:Neoplasm Transplantation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011379:Prognosis; D011485:Protein Binding; D019707:Receptors, Chemokine / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000872:Anthocyanins; D000911:Antibodies, Monoclonal; D005419:Flavonoids; D005960:Glucosides; D016023:Integrins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D019707:Receptors, Chemokine; C000596494:cyanidin 3-O-glucopyranoside; D051997:ADP-ribosyl Cyclase 1; D002118:Calcium