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Chronic Lymphocytic Leukemia

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

Leukemia volume 29, pages 356–368 (2015)Cite this article

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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 Ca2+ 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.

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Acknowledgements

We thank M Lamusta and K Gizzi for excellent technical support. This work is dedicated to the memory of Christian Usseglio Mattiet. This work is supported by grants from the Italian Ministries of Education, University and Research (Futuro in Ricerca 2008 no. RBFR08ATLH and 2012 no. RBFR12D1CB, PRIN 2009 no. 2009LMEEEH_002), the Italian Ministry of Health (Bando Giovani Ricercatori 2008 no. GR-2008-1138053, GR-2010-2317594 and GR-2011-02349282), the Associazione Italiana per la Ricerca sul Cancro Foundation (IG 12754) and Cariplo Foundation (grant #2012-0689).

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Authors and Affiliations

  1. Department of Medical Sciences, School of Medicine and Human Genetics Foundation, University of Torino, Torino, Italy

    T Vaisitti, V Audrito, S Serra, R Buonincontri & S Deaglio

  2. Human Genetics Foundation (HuGeF), Torino, Italy

    T Vaisitti, V Audrito, S Serra, R Buonincontri, A Pagnani & S Deaglio

  3. DIMES-Section of Biochemistry AND CEBR, University of Genova, Genova, Italy

    G Sociali, E Mannino & S Bruzzone

  4. Centro di Riferimento Oncologico (CRO) IRCCS, Aviano, Italy

    A Zucchetto, E Tissino & V Gattei

  5. Division of Hematology, University of Torino, Azienda Universitaria Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy

    C Vitale & M Coscia

  6. Institute of Biophysics, CNR, Genova, Italy

    C Usai

  7. Institute of Cancer & Genetics, Cardiff University, Heath Park, Cardiff, UK

    C Pepper

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Correspondence to S Deaglio.

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Vaisitti, T., Audrito, V., Serra, S. et al. The enzymatic activities of CD38 enhance CLL growth and trafficking: implications for therapeutic targeting. Leukemia 29, 356–368 (2015). https://doi.org/10.1038/leu.2014.207

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