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^L252P mutation caused prolonged persistence of antigen-specific serum IgM and elevated numbers of antigen-specific IgM plasma cells. Myd88^L252P-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^L252P 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^L252P 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.

信号转接头MYD88的TIR域中的高度复发性体细胞L265P突变组成性激活NF-κB。它几乎发生在所有患有Waldenström巨球蛋白血症（WM）的人类患者中，这是一种由表达IgM的细胞引起的B细胞恶性肿瘤。在这里，我们向小鼠Myd88基因座的直系同源位置L252P引入了脯氨酸点突变的诱导型亮氨酸。当在B细胞发育早期引入突变时，B细胞正常发育。然而，随着年龄的增长，在脾脏和骨骼中积累表达IgM的浆细胞，导致血清IgM滴度升高20倍以上。在免疫中被导入生发中心B细胞时，Myd88 ^L252P突变导致抗原特异性血清IgM的持久存在和抗原特异性IgM浆细胞数量的增加。表达Myd88 ^L252P的B细胞正常切换，但表达其他免疫球蛋白同种型的浆细胞数量并未增加，这表明观察到的细胞扩增可能需要IgM表达。为了测试Myd88 ^L252P突变是否会引起克隆扩增，我们将其引入了一小部分CD19阳性B细胞。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，并伴随着克隆表达的浆细胞的扩增，这些浆细胞主要表达高度变异的VDJ区。综上所述，我们的数据表明Myd88 ^L252P 突变足以促进表达IgM的浆细胞的异常存活和扩增，这反过来又会引起意义不明的IgM单克隆丙种球蛋白病（MGUS），即WM之前的恶变前状态。