The enzymatic activities of CD38 enhance CLL growth and trafficking: implications for therapeutic targeting

• Published in: Leukemia 2015-02, Vol.29 (2), p.356-368
• Main Authors: Vaisitti, T, Audrito, V, Serra, S, Buonincontri, R, Sociali, G, Mannino, E, Pagnani, A, Zucchetto, A, Tissino, E, Vitale, C, Coscia, M, Usai, C, Pepper, C, Gattei, V, Bruzzone, S, Deaglio, S
• Format: Article
• Language: English
• Subjects: 42/70; 45; 45/61; 59; 59/57; 631/67/1990/283/1895; 64; 64/60; 96; 96/31; Adenosine diphosphate; ADP-ribosyl Cyclase 1 - genetics; ADP-ribosyl Cyclase 1 - metabolism; Amino acids; Animals; Anthocyanins - pharmacology; Antibodies, Monoclonal - pharmacology; B cells; Calcium; Calcium - metabolism; Calcium ions; Cancer Research; Care and treatment; CD38 antigen; Cell Adhesion; Cell Movement; Cell Proliferation; Cellular proteins; Chemokine receptors; Chemotaxis; Chemotherapy; Chronic lymphocytic leukemia; Clinical trials; Critical Care Medicine; Cyclic ADP-ribose; Development and progression; Enzymatic activity; Enzyme inhibitors; Enzymes; Flavonoids; Flavonoids - pharmacology; Gene expression; Gene Expression Profiling; Genetic aspects; Glucosides - pharmacology; Health aspects; Hematology; Homing; Humans; Integrins; Integrins - metabolism; Intensive; Internal Medicine; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - therapy; Lymphatic leukemia; Male; Medicine; Medicine & Public Health; Membrane Microdomains; Mice; Mice, Inbred NOD; Mice, SCID; Mice, Transgenic; Microscopy, Fluorescence; Monoclonal antibodies; Mutation; NAD; Neoplasm Transplantation; Oncology; original-article; Physiological aspects; Platelet Endothelial Cell Adhesion Molecule-1 - metabolism; Prognosis; Protein Binding; Receptors; Receptors, Chemokine - metabolism; Ribose; Signal Transduction; Therapeutic applications; Therapeutic targets; Xenografts; Xenotransplantation
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2014.207

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.