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Chronic Lymphocytic Leukemia

A novel role of the CX3CR1/CX3CL1 system in the cross-talk between chronic lymphocytic leukemia cells and tumor microenvironment

Leukemia volume 25, pages 1268–1277 (2011)Cite this article

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Abstract

Several chemokines/chemokine receptors such as CCR7, CXCR4 and CXCR5 attract chronic lymphocytic leukemia (CLL) cells to specific microenvironments. Here we have investigated whether the CX3CR1/CX3CL1 axis is involved in the interaction of CLL with their microenvironment. CLL cells from 52 patients expressed surface CX3CR1 and CX3CL1 and released constitutively soluble CX3CL1. One third of these were attracted in vitro by soluble CX3CL1. CX3CL1-induced phosphorylation of PI3K, Erk1/2, p38, Akt and Src was involved in induction of CLL chemotaxis. Leukemic B cells upregulated CXCR4 upon incubation with CX3CL1 and this was paralleled by increased chemotaxis to CXCL12. Akt phosphorylation was involved in CX3CL1-induced upregulation of CXCR4 on CLL. In proliferation centers from CLL lymph node and bone marrow, CX3CL1 was expressed by CLL cells whereas CX3CR1 was detected in CLL and stromal cells. Nurselike cells (NLCs) generated from CLL patient blood co-expressed surface CX3CR1 and CX3CL1, but did not secrete soluble CX3CL1. Only half of NLC cell fractions were attracted in vitro by CX3CL1. In conclusion, the CX3CR1/CX3CL1 system may contribute to interactions between CLL cells and tumor microenvironment by increasing CXCL12-mediated attraction of leukemic cells to NLC and promoting directly adhesion of CLL cells to NLC.

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Acknowledgements

We thank Dr Salvatore Casciaro, from the Department of Internal Medicine, University of Genova, Italy, for providing a few CLL samples, Dr A Pistorio from the Epidemiology and Biostatistics Unit, IRCSS G. Gaslini of Genoa, Italy, for the help in statistical analysis, Dr Carla Guarnotta for the help in immunohistochemical analysis and Dr Paolo Fardin for supervising PCR experiments. The work has been supported by grants from Progetti Strategici Oncologici, Ministero della Salute 2006 to AC and VP, from AIRC to VP, and from Bando Giovani Ricercatori 2008, Ministero della Salute and AIRC to SD.

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Author notes

  1. V Pistoia and A Corcione: These authors contributed equally to this work

Authors and Affiliations

  1. Laboratory of Oncology, IRCCS G. Gaslini, Genova, Italy

    E Ferretti, V Pistoia & A Corcione

  2. Department of Internal Medicine, Laboratory of Phagocyte Physiopathology and Inflammation, University of Genova, Genova, Italy

    M Bertolotto & L Ottonello

  3. Department of Genetics, Biology & Biochemistry, Human Genetics Foundation (HuGeF), University of Torino, Torino, Italy

    S Deaglio & V Audrito

  4. Department of Health Science, Tumor Immunology Unit, Human Pathology Section, University of Palermo, Palermo, Italy

    C Tripodo

  5. Department of Human Anatomy and Histology, University of Bari, Bari, Italy

    D Ribatti

  6. Laboratory of Molecular Biology, Gaslini Institute, Genova, Italy

    F Blengio

  7. Medical Oncology C, National Cancer Research Institute, Genova, Italy

    S Matis

  8. Laboratory of Diagnostics of Lymphoproliferative Disorders, National Cancer Research Institute, Genova, Italy

    S Zupo

  9. Division of Hematology, Department of Clinical and Experimental Medicine, Amedeo Avogadro, University of Eastern Piedmont, Novara, Italy

    D Rossi & G Gaidano

  10. Department of Genetics, Biology & Biochemistry, Research Center for Experimental Medicine (CeRMS), University of Torino, Torino, Italy

    F Malavasi

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Correspondence to A Corcione.

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Ferretti, E., Bertolotto, M., Deaglio, S. et al. A novel role of the CX3CR1/CX3CL1 system in the cross-talk between chronic lymphocytic leukemia cells and tumor microenvironment. Leukemia 25, 1268–1277 (2011). https://doi.org/10.1038/leu.2011.88

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