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Chronic Lymphocytic Leukemia

CD38 increases CXCL12-mediated signals and homing of chronic lymphocytic leukemia cells

Leukemia volume 24, pages 958–969 (2010)Cite this article

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Abstract

Homing of chronic lymphocytic leukemia (CLL) cells to sites favoring growth, a critical step in disease progression, is principally coordinated by the CXCL12/CXCR4 axis. A cohort of 62 CLL patients was divided into migrating and nonmigrating subsets according to chemotaxis toward CXCL12. Migrating patients phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) proteins more than nonmigrating patients (P<0.0002). CD38 expression was the parameter most strongly associated with heightened CXCL12 signaling (P<0.0001), confirmed by independent statistical approaches. Consistent with this observation, CD38− CLL cells in samples with bimodal CD38 expression responded less to CXCL12 than the intact clone (P=0.003). Furthermore, lentivirus-induced de novo expression of CD38 was paralleled by increased responses to CXCL12, as compared with cells infected with a control virus. CD38 ligation with agonistic monoclonal antibodies (mAbs) enhanced CXCL12 signaling, whereas blocking anti-CD38 mAbs inhibited chemokine effects in vitro. This is attributed to physical proximity on the membrane between CD38 and CXCR4 (the CXCL12 receptor), as shown by (i) coimmunoprecipitation and (ii) confocal microscopy experiments. Blocking anti-CD38 mAbs significantly compromised homing of CLL cells from blood to lymphoid organs in a mouse model. These results indicate that CD38 synergizes with the CXCR4 pathway and support the working hypothesis that migration is a central step in disease progression.

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Acknowledgements

The expert technical assistance of Ms K Gizzi is gratefully acknowledged. We thank Dr A Funaro (University of Turin, Italy) for purifying IB4 mAb. This work was supported by the Associazione Italiana Ricerca Cancro (AIRC; S.D.), CLL Global Research Foundation (S.D.), Compagnia SanPaolo, Progetti Ricerca Interesse Nazionale (PRIN; F.M.), University of Turin (S.D. and F.M.), Fondazione ‘Guido Berlucchi’ (F.M.), Regione Piemonte (S.D., T.V. and F.M.), Leukaemia Research UK (P.B. and C.P.) and Leukaemia Research Appeal for Wales (P.B. and C.P.). The Fondazione Internazionale Ricerche Medicina Sperimentale (FIRMS) provided financial and administrative assistance. T.V. is supported by a Federazione Italiana Ricerca Cancro (FIRC) fellowship. S.A. is a student of the Ph.D. program in Advanced Techniques in the Localization of Human Tumors (University of Turin).

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Authors and Affiliations

  1. Department of Genetics, Biology and Biochemistry, University of Torino Medical School, Turin, Italy

    T Vaisitti, S Aydin, F Cottino, A L Horenstein, F Malavasi & S Deaglio

  2. Research Center for Experimental Medicine (CeRMS), University of Torino Medical School, Turin, Italy

    T Vaisitti, S Aydin, F Cottino, L Bonello, A L Horenstein, F Malavasi & S Deaglio

  3. Division of Hematology, Department of Clinical and Experimental Medicine and BRMA, Amedeo Avogadro University of Eastern Piedmont and AOU Maggiore della Carità, Novara, Italy

    D Rossi & G Gaidano

  4. Department of Medicine and Experimental Oncology, University of Torino Medical School, Turin, Italy

    L Bergui

  5. IRCCS ‘Casa Sollievo della Sofferenza’ Hospital, San Giovanni Rotondo, Italy

    G D'Arena

  6. Department of Hematology, Cardiff University, Cardiff, UK

    P Brennan & C Pepper

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  1. T Vaisitti
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Correspondence to S Deaglio.

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Vaisitti, T., Aydin, S., Rossi, D. et al. CD38 increases CXCL12-mediated signals and homing of chronic lymphocytic leukemia cells. Leukemia 24, 958–969 (2010). https://doi.org/10.1038/leu.2010.36

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