The SLAMF3 rs509749 polymorphism correlates with malignant potential in multiple myeloma

• Published in: Experimental hematology Vol. 90; pp. 72 - 79
• Main Authors: Ishibashi, Mariko, Sunakawa-Kii, Mika, Kaito, Yuta, Kinoshita, Ryosuke, Asayama, Toshio, Kuribayashi, Yasuko, Inokuchi, Koiti, Morita, Rimpei, Tamura, Hideto
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.10.2020
• Subjects: Alleles; Animals; Cell Line, Tumor; Disease-Free Survival; Female; Genotype; Humans; Japan - epidemiology; Male; MAP Kinase Signaling System - genetics; Mice; Multiple Myeloma - genetics; Multiple Myeloma - metabolism; Multiple Myeloma - mortality; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Polymorphism, Single Nucleotide; Signaling Lymphocytic Activation Molecule Family - genetics; Signaling Lymphocytic Activation Molecule Family - metabolism; Survival Rate; Japan
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/j.exphem.2020.08.006

The signaling lymphocytic activation molecule family 3 (SLAMF3) is highly expressed on plasma cells from patients with multiple myeloma (MM) and induces high malignant potential by ERK signaling mediated via the interaction with adaptor proteins SHP2 and GRB2. This study focused on the single-nucleotide polymorphism (SNP) of the SLAMF3 gene (rs509749, 1804A>G, M602V) in MM. The SNP G allele was a major type, and the frequencies of the GG, GA, and AA genotypes were 61.8%, 29.4%, and 8.8%, respectively, in patients with MM, which was almost the same as in healthy the control group in the Japanese population. Interestingly, patients with GG genotypes had significantly shorter overall survival times than patients with GA/AA genotypes. Consistent with those results, SLAMF3-overexpressing KMS-34 cells with the G allele (V602) had higher cell proliferation potential and were more resistant to anti-MM agents than those with the A allele (M602). When those cells were subcutaneously inoculated into NOG mice, tumor sizes in mice receiving V602 cells rapidly increased, and survival was significantly shorter than in mice injected with M602 cells. Furthermore, SLAMF3 V602 molecules bound more tightly to SHP2 and GRB2, with increased SHP2 and ERK phosphorylation compared with M602 cells. The mRNA expression of cell cycle-related genes (CCND1 and CCNE1) and anti-apoptotic genes (BCL2L and p21) was increased in V602 cells compared with M602 cells. The results thus suggested that the G allele of SLAMF3 SNP rs509749 may be associated with MM disease progression. •The SLAMF3 rs509749 GG genotype predominates in Japanese patients with MM and the control group.•GG genotype patients with MM had shorter overall survival time than the GA/AA group.•SLAMF3 V602-expressing MM cells had more aggressive behavior than M602 cells.•Affinity for SHP2 and GRB2 induced ERK phosphorylation in SLAMF3 V602 cells.•ERK signaling activation promoted malignant progression in SLAMF3 V602 cells.