Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
Biology of Malignant Lymphomas, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
Front Immunol. 2020 Dec 1;11:602868. doi: 10.3389/fimmu.2020.602868. eCollection 2020.
A highly recurrent somatic L265P mutation in the TIR domain of the signaling adapter MYD88 constitutively activates NF-κB. It occurs in nearly all human patients with Waldenström's macroglobulinemia (WM), a B cell malignancy caused by IgM-expressing cells. Here, we introduced an inducible leucine to proline point mutation into the mouse Myd88 locus, at the orthologous position L252P. When the mutation was introduced early during B cell development, B cells developed normally. However, IgM-expressing plasma cells accumulated with age in spleen and bone, leading to more than 20-fold elevated serum IgM titers. When introduced into germinal center B cells in the context of an immunization, the Myd88 mutation caused prolonged persistence of antigen-specific serum IgM and elevated numbers of antigen-specific IgM plasma cells. Myd88-expressing B cells switched normally, but plasma cells expressing other immunoglobulin isotypes did not increase in numbers, implying that IgM expression may be required for the observed cellular expansion. In order to test whether the Myd88 mutation can cause clonal expansions, we introduced it into a small fraction of CD19-positive B cells. In this scenario, five out of five mice developed monoclonal IgM serum paraproteins accompanied by an expansion of clonally related plasma cells that expressed mostly hypermutated VDJ regions. Taken together, our data suggest that the Myd88 mutation is sufficient to promote aberrant survival and expansion of IgM-expressing plasma cells which in turn can cause IgM monoclonal gammopathy of undetermined significance (MGUS), the premalignant condition that precedes WM.
在信号转导接头 MYD88 的 TIR 结构域中，一种高度频发的体细胞 L265P 突变会持续激活 NF-κB。该突变几乎存在于所有患有华氏巨球蛋白血症（WM）的人类患者中，WM 是一种由 IgM 表达细胞引起的 B 细胞恶性肿瘤。在这里，我们在小鼠 Myd88 基因座的同源位置 L252P 处引入了一个可诱导的亮氨酸到脯氨酸点突变。当该突变在 B 细胞发育早期引入时，B 细胞正常发育。然而，随着年龄的增长，IgM 表达的浆细胞在脾脏和骨骼中积累，导致血清 IgM 滴度升高 20 多倍。当在免疫接种的情况下引入生发中心 B 细胞时，Myd88 突变导致抗原特异性血清 IgM 的持续延长和抗原特异性 IgM 浆细胞数量的增加。Myd88 表达的 B 细胞正常转换，但表达其他免疫球蛋白同种型的浆细胞数量没有增加，这意味着 IgM 表达可能是观察到的细胞扩增所必需的。为了测试 Myd88 突变是否可以引起克隆扩增，我们将其引入一小部分 CD19 阳性 B 细胞中。在这种情况下，五分之五的小鼠产生了单克隆 IgM 血清副蛋白，并伴有克隆相关浆细胞的扩增，这些浆细胞主要表达高突变的 VDJ 区。综上所述，我们的数据表明，Myd88 突变足以促进 IgM 表达浆细胞的异常存活和扩增，进而导致 IgM 单克隆丙种球蛋白病（MGUS），即 WM 之前的癌前状态。
