Farre Diaz, C. | Search bioRxiv

bioRxiv2024

In vivo sequential mutagenesis in germinal center B cells using a dual-recombinase approach: FOXO1 re-expression upon FOXO1 knockout rescues class switch recombination

Modeling complex (patho)physiological processes by sequential mutagenesis in mice is limited by the lack of optimized genetic tools and complex breeding strategies. We present a new Cre/DreERT2 dual-recombinase germinal center B-cell (GCBC)- specific strain, with co-expression of the recombinases from a single allele. This enables highly efficient Cre-mediated FOXO1 knockout followed by time-controlled, efficient Dre-mediated FOXO1 re-expression and functional rescue in GCBCs, demonstrating suitability for precise targeted sequential mutagenesis in vivo.

immunology↗

bioRxiv2021

Preclinical models of human multiple myeloma subgroups

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.

cancer biology↗