Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan.
Department of Hematology, Nippon Medical School, Tokyo, Japan.
Exp Hematol. 2020 Oct;90:72-79. doi: 10.1016/j.exphem.2020.08.006. Epub 2020 Aug 17.
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 (V) had higher cell proliferation potential and were more resistant to anti-MM agents than those with the A allele (M). When those cells were subcutaneously inoculated into NOG mice, tumor sizes in mice receiving V cells rapidly increased, and survival was significantly shorter than in mice injected with M cells. Furthermore, SLAMF3 V molecules bound more tightly to SHP2 and GRB2, with increased SHP2 and ERK phosphorylation compared with M cells. The mRNA expression of cell cycle-related genes (CCND1 and CCNE1) and anti-apoptotic genes (BCL2L and p21) was increased in V cells compared with M cells. The results thus suggested that the G allele of SLAMF3 SNP rs509749 may be associated with MM disease progression.
信号淋巴细胞激活分子家族 3（SLAMF3）在多发性骨髓瘤（MM）患者的浆细胞中高度表达，并通过与衔接蛋白 SHP2 和 GRB2 的相互作用介导的 ERK 信号诱导高恶性潜能。本研究集中于 SLAMF3 基因（rs509749，1804A>G，M602V）的单核苷酸多态性（SNP）在 MM 中的作用。SNP G 等位基因是主要类型，在 MM 患者中 GG、GA 和 AA 基因型的频率分别为 61.8%、29.4%和 8.8%，与日本人群中的健康对照组几乎相同。有趣的是，GG 基因型的患者总生存时间明显短于 GA/AA 基因型的患者。与这些结果一致，携带 G 等位基因（V）的 SLAMF3 过表达 KMS-34 细胞具有更高的细胞增殖潜力，并且对抗 MM 药物的耐药性高于携带 A 等位基因（M）的细胞。当将这些细胞皮下接种到 NOG 小鼠中时，接受 V 细胞的小鼠的肿瘤大小迅速增大，并且存活时间明显短于接受 M 细胞的小鼠。此外，与 M 细胞相比，SLAMF3 V 分子与 SHP2 和 GRB2 的结合更紧密，并且 SHP2 和 ERK 磷酸化增加。与 M 细胞相比，V 细胞中细胞周期相关基因（CCND1 和 CCNE1）和抗凋亡基因（BCL2L 和 p21）的 mRNA 表达增加。结果表明，SLAMF3 SNP rs509749 的 G 等位基因可能与 MM 疾病进展有关。
