Chronic lymphocytic leukemia (CLL) is characterized by the expansion of a monoclonal population of mature CD5+/CD23+ B lymphocytes, with a highly variable clinical course. Gene expression profiling studies identified SLAMF-1 (signaling lymphocytic activation molecule aka CD150) as part of the genetic signature characterizing CLL patients with favorable prognosis. Human SLAMF-1 is the prototype member of a family of receptors that act as co-activators through self-interactions on hematopoietic cell surface. SLAMF-1 activation is essential for full T cell functions, including cytokine secretion and development. The role of SLAMF-1 in antigen presenting cells, including B cells, is less well characterized, though it is known that the molecule initiates a signaling pathway that leads to B cell proliferation or CD95-mediated apoptosis. More recently, SLAMF-1 has been attributed a novel function as a microbial sensor that regulates bacterial phagosome functions by recruiting a supra-molecular complex, part of the ubiquitous cellular autophagic machinery. The analysis on the CD19+ fraction of 292 clinically and molecularly characterized CLL patients revealed highly variable levels of SLAMF-1 expression (1–95%). Statistical analyses of the data indicated that patients characterized by a good prognosis (in terms of disease stage at diagnosis or treatment requirements) express higher levels of SLAMF-1 compared to the other subgroups. Moreover, patients with > 6% SLAMF-1+/CD19+ CLL cells had a significantly longer treatment free survival (median 6.4 in SLAMF-1+ vs 1.2 years in SLAMF-1– patients, P=.002). Consistently, SLAMF-1 expression inversely correlates with CD38 and CD49d, two molecular markers of unfavorable prognosis, and positively associates with the presence of somatic mutations in the IgHV genes. Functional experiments showed that the engagement of SLAMF-1 by an agonistic mAb started a well-characterized signaling pathway. Co-immunoprecipitation experiments demonstrated a direct interaction between the receptor and the adaptor molecule EAT-2, with its consequent phosphorylation and the following downstream activation of Vav-1, p38 and JNK. Moreover, co-crosslinking of SLAMF-1 and sIgM prolonged the phosphorylation of p38 and JNK and resulted in an increased percentage of CLL cells undergoing apoptosis, as compared to either signals alone or the basal condition. Furthermore, the engagement of SLAMF-1 for a period of 6 hours led to an increased appearance of autophagic vesicles, as confirmed by confocal and transmission electron microscopy. The modulation of apoptosis and autophagy was mediated by the sequential phosphorylation of JNK and Bcl-2: the final result is the activation of Bcl-2 (phospho-Ser70) and the release of Beclin-1, an essential member of the autophagic complex. In conclusion, i) SLAMF-1 is expressed at higher levels by patients with a good prognosis, ii) and performs as an immunoreceptor on CLL cells, starting a signaling pathway that involves the adaptor molecule EAT-2, Vav-1 and MAP kinases, like p38 and JNK. iii) SLAMF-1+ CLL patients respond to receptor engagement modulating an autophagic pathway mediated by the phosphorylation of JNK and Bcl-2. Taken together, these results suggest that SLAMF-1 could represent a novel marker for the subset of CLL patients characterized by an indolent clinical course and highlight a hypothetical link between the activation of the autophagic process and a better clinical outcome in CLL
Slamf-1/CD150 Is a Signaling Receptor Expressed by a Subset of Chronic Lymphocytic Leukemia Patients Characterized by a Favorable Prognosis / Cinzia Bologna; Roberta Buonincontri; Sara Serra; Tiziana Vaisitti; Valentina Audrito; Davide Brusa; Davide Rossi; Marta Coscia; Gianluca Gaidano; Cox Terhorst; Silvia Deaglio. - In: BLOOD. - ISSN 0006-4971. - 120(2012), pp. 1770-1770. ((Intervento presentato al convegno 54th American Society of Hematology Annual Meeting and Exposition tenutosi a Atlanta, GA, USA nel 8-11 December 2012.