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. 2008 May;22(5):980-8. doi: 10.1038/leu.2008.21. Epub 2008 Feb 21.

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 kappa-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Case-Control Studies
  • Cell Division
  • Disease Progression
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Leukemia, B-Cell / metabolism*
  • Leukemia, B-Cell / pathology
  • Phosphorylation
  • Receptors, Immunologic / analysis
  • Receptors, Immunologic / genetics*
  • Signal Transduction
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Receptors, Immunologic
  • leukocyte-associated immunoglobulin-like receptor 1
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases