多发性骨髓瘤（MM）是一种来源于发生中心（GC）经历过的浆细胞的肿瘤，由t（11；14）/ CCND1和t（4；14）/ MMSET亚型等不同的遗传亚组成。我们通过小鼠Ccnd1或MMSET与一种构成性活性Ikk2突变体的GC B细胞特异性共激活，模仿了人类MM中经常出现的次级NF-κB活化，生成了基因定义的亚组特异性的MM模型。Ccnd1 / Ikk2ca和MMSET / Ikk2ca小鼠随着年龄的增长发展出明显的、克隆限制的浆细胞增殖，伴随有血清M蛋白的产生、骨髓不足和骨损伤。转基因浆细胞在体内可以传播，并显示出与其人类MM同伴相似的明显转录谱，因此我们证明了将涉及MM亚组特异染色体易位的基因表达定位在小鼠GC B细胞中可以转化成具有不同MM样疾病的能力，并重现了人类肿瘤的关键特征，这打开了对不同MM亚组的发病机理和治疗脆弱性的更好理解之路。

Multiple myeloma (MM), a tumor of germinal center (GC)-experienced plasma cells, comprises distinct genetic subgroups, such as the t(11;14)/CCND1 and the t(4;14)/MMSET subtype. We have generated genetically defined, subgroup-specific MM models by the GC B cell-specific coactivation of mouse Ccnd1 or MMSET with a constitutively active Ikk2 mutant, mimicking the secondary NF-κB activation frequently seen in human MM. Ccnd1/Ikk2ca and MMSET/Ikk2ca mice developed a pronounced, clonally restricted plasma cell outgrowth with age, accompanied by serum M spikes, bone marrow insufficiency, and bone lesions. The transgenic plasma cells could be propagated in vivo and showed distinct transcriptional profiles, resembling their human MM counterparts. Thus, we show that targeting the expression of genes involved in MM subgroup-specific chromosomal translocations into mouse GC B cells translates into distinct MM-like diseases that recapitulate key features of the human tumors, opening the way to a better understanding of the pathogenesis and therapeutic vulnerabilities of different MM subgroups.