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Chronic Lymphocytic Leukemia

Lack of the leukocyte-associated Ig-like receptor-1 expression in high-risk chronic lymphocytic leukaemia results in the absence of a negative signal regulating kinase activation and cell division

Leukemia volume 22, pages 980–988 (2008)Cite this article

Abstract

In this study, we analysed 30 patients with B-cell chronic lymphocytic leukaemia (CLL), compared with 10 healthy donors, for the expression and function of the leukocyte-associated Ig-like receptor-1 (LAIR-1). LAIR-1 is an inhibitory receptor containing a cytoplasmic tyrosine-based inhibitory motif (ITIM) that binds to the SH2 domain of phosphatases, leading to dephosphorylation of different kinases. Constitutive activation of c-Jun aminoterminal kinase (JNK), p38 mitogen-activated protein kinase and extracellular signal-regulated kinase, has been reported in CLL. We show that LAIR-1 is absent in high–risk (HR) CLL and differently expressed on intermediate- and low-risk CLL and the intensity of expression, which is always significantly lower than in healthy donors, correlates with disease stage and progression. Interestingly, both constitutive and sIgM-induced phosphorylation of p38 and JNK is inhibited by LAIR-1 through an ITIM-dependent signal, as demonstrated by the use of specific ITIM-binding peptides; importantly, this inhibitory signal is missing when LAIR-1 is not expressed as occurs in HR CLL. Moreover, engagement of LAIR-1 blocks constitutive and sIgM-induced Akt phosphorylation, besides nuclear factor κ-B nuclear translocation, and prevents CLL division. These results suggest that CLL lacking LAIR-1 may miss one of the molecular mechanisms controlling B-cell activation and proliferation.

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Acknowledgements

This study was supported by the Italian Ministero della Salute (AP and MRZ) Coordinated Grant Special Project), by the Italian Istituto Superiore di Sanità (IV National Project on AIDS Research), by the Italian Association for Cancer Research (AP and MRZ) and by Compagnia San Paolo 2007.0265 to AP.

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Authors and Affiliations

  1. Laboratory of Experimental Oncology D, National Institute for Cancer Research, Genoa, Italy

    A Poggi

  2. Department of Clinical Oncology and Hematology, Laboratory of Hematology, University of Genoa, Genoa, Italy

    S Catellani

  3. Department of Internal Medicine, University of Genoa, Genoa, Italy

    A Bruzzone

  4. Department of Oncology, Università Vita-Salute, San Raffaele Scientific Institute, Milan, Italy

    F Caligaris-Cappio

  5. Department of Clinical Oncology and Hematology, University of Genoa, Genoa, Italy

    M Gobbi

  6. Laboratory of Tumor Immunology, San Raffaele Scientific Institute, Milan, Italy

    M R Zocchi

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  1. A Poggi
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  2. S Catellani
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  4. F Caligaris-Cappio
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Correspondence to A Poggi.

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Poggi, A., Catellani, S., Bruzzone, A. et al. Lack of the leukocyte-associated Ig-like receptor-1 expression in high-risk chronic lymphocytic leukaemia results in the absence of a negative signal regulating kinase activation and cell division. Leukemia 22, 980–988 (2008). https://doi.org/10.1038/leu.2008.21

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