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.
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.
Poggi
A
A
Laboratory of Experimental Oncology D, National Institute for Cancer Research, Genoa, Italy. alessandro.poggi@istge.it
Catellani
S
S
Bruzzone
A
A
Caligaris-Cappio
F
F
Gobbi
M
M
Zocchi
M R
MR
D016022:Case-Control Studies; D002455:Cell Division; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D015448:Leukemia, B-Cell / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011971:Receptors, Immunologic / Q000032:analysis / Q000235:genetics*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D011971:Receptors, Immunologic; C108073:leukocyte-associated immunoglobulin-like receptor 1; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases