Preclinical models of human multiple myeloma subgroups

Abstract

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 subgroup-specific MM models by the GC B cell-specific co-activation of Ccnd1 or MMSET with a constitutively active Ikk2 mutant, mimicking the secondary NF{kappa}B 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 transcriptional profiles resembling their human counterparts. Thus, we show that Ccnd1 and MMSET cooperate with NF{kappa}B in MM pathogenesis, considering for the first time the genetic heterogeneity of MM for the generation of preclinical models.