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

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 leukocyteassociated 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 mitogenactivated 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 j-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.

Clinical significance of LAIR1 (CD305) as assessed by flow cytometry in a prospective series of patients with chronic lymphocytic leukemia

“…Furthermore, consistently with our findings, Poggi et al recently observed that the expression of LAIR1 is higher in patients with low-risk CLL. 16 In our series, LAIR1 expression allowed us to discriminate different set of patients with significant biological and clinical differences, confirming that LAIR1 -patients were more likely to have a worse clinical stage at diagnosis and adverse biological factors, such as unmutated IGHV genes, CD38 + , or highrisk cytogenetic lesions. 16,17 In the last years several studies have focused on the identification of biological markers that could be easily used to foresee the prognosis of CLL patients.…”

“…16 In our series, LAIR1 expression allowed us to discriminate different set of patients with significant biological and clinical differences, confirming that LAIR1 -patients were more likely to have a worse clinical stage at diagnosis and adverse biological factors, such as unmutated IGHV genes, CD38 + , or highrisk cytogenetic lesions. 16,17 In the last years several studies have focused on the identification of biological markers that could be easily used to foresee the prognosis of CLL patients. Many new immunophenotypic markers have been proposed for identifying high-risk patients, 11 in addition to historical ones, such as CD38 and ZAP-70.…”

“…On the other hand, prolonged BCR-or CD40-stimulation induces down-regulation of LAIR1 on naïve B cells in vitro, 15 suggesting an inhibitory role for LAIR1 on BCR signaling, as for other B-cell inhibitory receptors, such as CD22 and FcgRIIb. 15 16 Furthermore, in vitro studies confirmed that collagen produced by lymph node-derived mesenchymal stromal cells was able to inhibit B-cell functions through LAIR1 engagement. 26 Altogether these data strengthen and increase the appeal of LAIR1 having an active role in the pathophysiology of CLL with special emphasis on microenvironmental interactions inducing BCR activation.…”

“…13,14 LAIR1 expression varies during B-cell differentiation and has recently been demonstrated in patients with CLL. 15,16 The in-vivo role of LAIR1 in B cells consists in its inhibiting Bcell receptor (BCR)-mediated signaling 15 and in controlling kinase pathways involved in cell proliferation. 13 Recently, two studies performed in CLL patients showed that LAIR1 is more The association of LAIR1 expression with commonly recognized clinical and biological variables, and its prognostic role in patients with CLL is still unknown.…”

Defective Stromal Remodeling and Neutrophil Extracellular Traps in Lymphoid Tissues Favor the Transition from Autoimmunity to Lymphoma

“…Moreover, lpr/lpr/Sparc −/− mice showed NF-κB activation as well as BCR activation, which are characteristic of CLL clones, indicating that environment-mediated signals triggered NF-κB independent of intrinsic BCR activity ( 32 ). Underscoring the importance of microenvironmental control in CLL progression, the expression of LAIR-1 in transformed CD5 + B cells is progressively lost with increasing CLL clone aggressiveness ( 54 ). Unfortunately, the lack of LAIR-1 expression in murine B cells ( 48 ) did not allow us to directly test its role in our model.…”