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Persistent CD49d engagement in circulating CLL cells: a role for blood-borne ligands?

Leukemia volume 30, pages 513–517 (2016)Cite this article

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CD49d, the α-chain of the integrin heterodimer α4β1 (CD49d/CD29) is expressed on cell surface of ~40% of chronic lymphocytic leukemia (CLL) cases. It mediates both cell–cell and cell–matrix adhesion through binding to the vascular cell adhesion molecule-1 (VCAM-1) and fibronectin (FN), respectively. These interactions regulate CLL cell recirculation from the blood stream to tissue sites, as well as the transmission to CLL cells of signals of pro-survival and resistance to drug-induced apoptosis.1 Consistent with this functional role in CLL, a recent worldwide meta-analysis carried out on a large patient cohort, definitely demonstrated the independent prognostic relevance of CD49d in this disease.2

Although the most relevant cell interactions in CLL occur in lymph nodes and bone marrow (BM), specific signaling pathways (for example, NF-κB and MAPK pathways) have been found to be activated also in peripheral blood (PB)-derived CLL cells.3 This phenomenon suggests that the blood stream may represent a still poorly investigated source of soluble factors allegedly involved in the stimulation of circulating/tissue released CLL cells.3 Here, we revealed that CD49d-expressing circulating CLL cells have a phosphoproteomic profile consistent with a continuous CD49d engagement by blood-borne-specific ligands.

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Acknowledgements

This work is supported in part by Ricerca Finalizzata I.R.C.C.S., Ministero della Salute, Rome, Italy; Progetto Giovani Ricercatori n. GR-2009-1475467, no. GR-2011-02347441, no. GR-2011-02346826, Ministero della Salute, Rome, Italy; Associazione Italiana contro le Leucemie, linfomi e mielomi (AIL), Venezia Section, Pramaggiore Group, Italy; the Associazione Italiana Ricerca Cancro (AIRC), Grants No. IG-13227, Milan, Italy; ‘5 × 1000 Intramural Program’, Centro di Riferimento Oncologico, Aviano, Italy; Paracelsus Medical University Salzburg (E-13/18/093-HAR to TNH).

Author contributions

VG designed the study, coordinated the experiments and revised the manuscript; DB performed the experiments and wrote the manuscript; AZ, ET, CC, MDB, RB, SG and TNH performed part of the experiments and contributed to characterize samples and to data analysis; DM performed statistical analyses on RPPA results; AVM, VE and LL coordinated the RPPA study; FZ, GP, FDR and GDP provided well-characterized biological samples; all authors made substantial contribution to critical revision of the article and approved its final version.

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Authors and Affiliations

  1. Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, Aviano, Italy

    D Benedetti, E Tissino, C Caldana, M Dal Bo, R Bomben, D Marconi, A Zucchetto & V Gattei

  2. 3rd Medical Department, Laboratory for Immunological and Molecular Cancer Research, Paracelsus Medical University, Salzburg, Austria

    S Ganghammer & T N Hartmann

  3. Clinica Ematologica, Centro Trapianti e Terapie Cellulari Carlo Melzi, DISM, Azienda Ospedaliero-Universitaria S. M. Misericordia, Udine, Italy

    F Zaja

  4. Department of Internal Medicine and Hematology, Maggiore General Hospital, University of Trieste, Trieste, Italy

    G Pozzato

  5. Department of Hematology, University of Catania, Catania, Italy

    F Di Raimondo

  6. Division of Hematology, S. Eugenio Hospital and University of Tor Vergata, Roma, Italy

    G Del Poeta

  7. Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA

    A VanMeter, V Espina & L Liotta

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  1. D Benedetti
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  2. E Tissino
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  3. C Caldana
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  9. G Pozzato
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  14. A Zucchetto
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  16. L Liotta
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  17. V Gattei
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Corresponding author

Correspondence to V Gattei.

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The authors declare no conflict of interest.

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Supplementary Information accompanies this paper on the Leukemia website

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Benedetti, D., Tissino, E., Caldana, C. et al. Persistent CD49d engagement in circulating CLL cells: a role for blood-borne ligands?. Leukemia 30, 513–517 (2016). https://doi.org/10.1038/leu.2015.149

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