SLAMF1 regulation of chemotaxis and autophagy determines CLL patient response
Cinzia Bologna, … , Cox Terhorst, Silvia Deaglio
Cinzia Bologna, … , Cox Terhorst, Silvia Deaglio
Published November 30, 2015
Citation Information: J Clin Invest. 2016;126(1):181-194. https://doi.org/10.1172/JCI83013.
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SLAMF1 regulation of chemotaxis and autophagy determines CLL patient response

Abstract

Chronic lymphocytic leukemia (CLL) is a variable disease; therefore, markers to identify aggressive forms are essential for patient management. Here, we have shown that expression of the costimulatory molecule and microbial sensor SLAMF1 (also known as CD150) is lost in a subset of patients with an aggressive CLL that associates with a shorter time to first treatment and reduced overall survival. SLAMF1 silencing in CLL-like Mec-1 cells, which constitutively express SLAMF1, modulated pathways related to cell migration, cytoskeletal organization, and intracellular vesicle formation and recirculation. SLAMF1 deficiency associated with increased expression of CXCR4, CD38, and CD44, thereby positively affecting chemotactic responses to CXCL12. SLAMF1 ligation with an agonistic monoclonal antibody increased ROS accumulation and induced phosphorylation of p38, JNK1/2, and BCL2, thereby promoting the autophagic flux. Beclin1 dissociated from BCL2 in response to SLAMF1 ligation, resulting in formation of the autophagy macrocomplex, which contains SLAMF1, beclin1, and the enzyme VPS34. Accordingly, SLAMF1-silenced cells or SLAMF1lo primary CLL cells were resistant to autophagy-activating therapeutic agents, such as fludarabine and the BCL2 homology domain 3 mimetic ABT-737. Together, these results indicate that loss of SLAMF1 expression in CLL modulates genetic pathways that regulate chemotaxis and autophagy and that potentially affect drug responses, and suggest that these effects underlie unfavorable clinical outcome experienced by SLAMF1lo patients.

Authors

Cinzia Bologna, Roberta Buonincontri, Sara Serra, Tiziana Vaisitti, Valentina Audrito, Davide Brusa, Andrea Pagnani, Marta Coscia, Giovanni D’Arena, Elisabetta Mereu, Roberto Piva, Richard R. Furman, Davide Rossi, Gianluca Gaidano, Cox Terhorst, Silvia Deaglio

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Figure 1

SLAMF1 expression is lost in a subset of CLL patients with a more aggressive form of the disease.

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SLAMF1 expression is lost in a subset of CLL patients with a more aggres...
(A) Dot plots showing CD19/SLAMF1 expression in 3 representative CLL patients. (B) SLAMF1 expression was analyzed in the CD19+/CD5+ fraction of PBMC preparations from normal donors. (C) Box plot showing cumulative data from 300 CLL patients and 12 normal donors. (D) Distribution of SLAMF1 expression according to disease stage or treatment conditions. Patients were grouped into stage A versus stages B+C, according to the Binet classification. (E) Distribution of SLAMF1 expression according to treatment (chemotherapy or chemoimmunotherapy). –, untreated; +, treated with chemotherapy or chemoimmunotherapy. The box plot on the right considers patients who received no treatment for a period of at least 60 months, as opposed to patients who were treated within 1 year of diagnosis. (F) Distribution of SLAMF1 expression according to molecular and cytogenetic markers. The mutational status of the IGHV genes (unmutated if >98% similar to the germline sequence) together with CD38 and CD49d expression were considered as molecular markers. The cut-off for CD38 and CD49d expression was 30%. When considering cytogenetic abnormalities, patients were grouped on the basis of favorable (13q- or no abnormalities) vs. unfavorable (11q- and 17p-) chromosomal deletions. (G) Kaplan Meyer curves showing the probability of TFS and OS of CLL patients categorized on the basis of SLAMF1 expression. The 6% cut-off was determined by recursive partitioning analysis. Statistical analyses (C–F) were performed using Mann-Whitney U test.