Mouse 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 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.

The genomic landscape of Vk*MYC myeloma highlights shared pathways of transformation between mice and humans

“…We are actively investigating the mechanism of transformation in the cases without reversion and will report the results separately. Moreover, the majority (93.3%) of Vk*MYC MM tumors, like human MM, have undergone class switch recombination to express IgG or IgA; and out of the five cases expressing IgM, four have less than 2% somatic hypermutation at the immunoglobulin loci and lack reversion of the transgenic stop codon, suggesting a germinal center independent tumor origin, or an early germinal center exit, as recently reported in MM that develops in various different crosses with Ikk2ca activated by IgG1-CRE 30 , 31 . In line with this, the proportion of SBS9 was significantly lower in IgM Vk*MYC mice compared to the others ( p = 0.002 using Wilcoxon test).…”

“…6F). Although this proportion is lower in comparison to the 80% we have previously reported for human MM and its progressive precursor conditions 6 , the significant discovery that Vk*MYC MM spontaneously develops APO-BEC mutagenesis is a critical finding, considering that no other mouse model of MM has been reported to spontaneously acquire an APOBEC mutational signature (see Methods) 30,31 . Importantly, no correlation was noted between the presence of APOBEC and AID signatures, in line with the distinct nature and role of these two deaminases Article https://doi.org/10.1038/s41467-024-48091-w (Supplementary Data 20).…”

“…These types of investigations would not be feasible in humans due to the long time frame and ethical considerations. In is important also to highlight that the Vk*MYC spontaneous genomic evolution and heterogenicity are in contrast to other genetically modified mouse models of cancer, where engineered expression of multiple oncogenes limits the selection for genomic diversity 30 , 31 . Prior studies identified continued MYC-dependence using mouse models of lymphoma and leukemia initiated by MYC 51 .…”

“…As tumors progress from de novo, to transplant to in vitro stage, we observed an increased genomic complexity associated with a higher gene expression proliferation index (GPI), a known adverse event in human MM 29 . Remarkably, in both human and murine PCs, GPI inversely correlated with immunoglobulin expression: Ig transcription progressively declined from normal PCs, to MGUSor monoclonal gammopathy described in two recent mouse models based on Ikk2ca activation in germinal center B cells - 30,31 , to newly diagnosed MMor de novo Vk*MYC or the Ikk2ca crosses -, to relapse/refractory MMor transplant Vk*MYC or 5TGM1 MM -to human or murine PC lines that grow in vitro, which generally lack Ig expression (Fig. 5B, C).…”

“…Raw WGS, Mate pair, WES and RNAseq datasets are available on NCBI Gene Expression Omnibus(RRID:SCR_005012) under accession number GSE255233 and on NCBI Sequence Read Archive (RRID:SCR_004891) under the NCBI BioProject accession number PRJNA938752 . Publicly available data from previous mouse models were imported and reanalyzed following the pipeline described above: BioProjects PRJNA560057 , PRJNA721176 , PRJNA910238 , PRJNA259862 , PRJNA845532 , PRJNA846769 , PRJNA881497 , PRJNA912227 and PRJNA759563 30 , 31 . A Source Data File is provided.…”