Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, CA, United States of America.
Department of Medicine, University of California, San Francisco, CA, United States of America.
PLoS One. 2022 Aug 4;17(8):e0270907. doi: 10.1371/journal.pone.0270907. eCollection 2022.
Multiple myeloma (MM), a malignancy of plasma cells (PCs), has diverse genetic underpinnings and in rare cases these include amplification of the lymphotoxin b receptor (Ltbr) locus. LTβR has well defined roles in supporting lymphoid tissue development and function through actions in stromal and myeloid cells, but whether it is functional in PCs is unknown. Here we showed that Ltbr mRNA was upregulated in mouse PCs compared to follicular B cells, but deficiency in the receptor did not cause a reduction in PC responses to a T-dependent or T-independent immunogen. However, LTβR overexpression (OE) enhanced PC formation in vitro after LPS or anti-CD40 stimulation. In vivo, LTβR OE led to increased antigen-specific splenic and bone marrow (BM) plasma cells responses. LTβR OE PCs had increased expression of Nfkb2 and of the NF-kB target genes Bcl2 and Mcl1, factors involved in the formation of long-lived BM PCs. Our findings suggest a pathway by which Ltbr gene amplifications may contribute to MM development through increased NF-kB activity and induction of an anti-apoptotic transcriptional program.
多发性骨髓瘤（MM）是一种浆细胞（PCs）的恶性肿瘤，其具有多种遗传基础，在极少数情况下，这些遗传基础包括淋巴毒素 b 受体（Ltbr）基因座的扩增。LTβR 在支持淋巴组织发育和功能方面具有明确的作用，其通过在基质细胞和髓样细胞中的作用发挥作用，但它在 PCs 中是否具有功能尚不清楚。在这里，我们发现与滤泡 B 细胞相比，Ltbr mRNA 在小鼠 PCs 中上调，但受体缺失不会导致对 T 依赖性或 T 非依赖性免疫原的 PC 反应减少。然而，LTβR 过表达（OE）增强了 LPS 或抗 CD40 刺激后体外 PC 的形成。在体内，LTβR OE 导致抗原特异性脾脏和骨髓（BM）浆细胞反应增加。LTβR OE PCs 表达了更多的 Nfkb2 以及 NF-κB 靶基因 Bcl2 和 Mcl1，这些基因参与了长寿 BM PCs 的形成。我们的研究结果表明，Ltbr 基因扩增可能通过增加 NF-κB 活性和诱导抗凋亡转录程序，从而促进 MM 的发展。
