The SLAMF3 rs509749 polymorphism correlates with malignant potential in multiple myeloma
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Published on: December 13, 2018
Mariko Ishibashi1, Mika Sunakawa-Kii2, Yuta Kaito2
1Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan.
Abstract:
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.
Insights
A specific gene variant in signaling lymphocytic activation molecule family 3 (SLAMF3) is linked to poorer outcomes in multiple myeloma (MM). This SLAMF3 SNP (rs509749) G allele promotes cancer cell growth and resistance to treatment, suggesting a role in MM progression.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- Signaling lymphocytic activation molecule family 3 (SLAMF3) is highly expressed in multiple myeloma (MM) plasma cells.
- SLAMF3 signaling, involving SHP2 and GRB2, contributes to MM malignancy and ERK pathway activation.
- Single-nucleotide polymorphisms (SNPs) in cancer-related genes can influence disease progression and patient outcomes.
Purpose of the Study:
- To investigate the association of the SLAMF3 gene single-nucleotide polymorphism (SNP) rs509749 (1804A>G, M602V) with multiple myeloma (MM).
- To evaluate the impact of the SLAMF3 rs509749 SNP genotypes on MM patient survival and disease progression.
- To determine the functional consequences of the SLAMF3 G allele (V602) on MM cell behavior and signaling pathways.
Main Methods:
- Genotyping analysis of the SLAMF3 rs509749 SNP in MM patients and healthy controls from the Japanese population.
- Correlation analysis between SLAMF3 genotypes and overall survival in MM patients.
- In vitro and in vivo studies using MM cell lines (KMS-34) with different SLAMF3 alleles (M602 vs. V602) and NOG mouse models.
Main Results:
- The G allele of SLAMF3 rs509749 was frequent in MM patients, with GG genotype associated with significantly shorter overall survival compared to GA/AA genotypes.
- SLAMF3-overexpressing cells with the G allele (V602) exhibited enhanced proliferation, increased resistance to anti-MM agents, and promoted tumor growth in vivo.
- The V602 variant showed increased binding to SHP2 and GRB2, leading to elevated SHP2 and ERK phosphorylation, and upregulated expression of cell cycle and anti-apoptotic genes.
Conclusions:
- The G allele of the SLAMF3 SNP rs509749 (V602) is associated with increased malignant potential and poorer survival in multiple myeloma patients.
- This genetic variant enhances MM cell proliferation, drug resistance, and tumor growth through altered SLAMF3-mediated signaling.
- SLAMF3 rs509749 SNP may serve as a potential biomarker for predicting MM disease progression and patient outcomes.
