Cyclin D2 Overexpression Recapitulates Mantle Cell Lymphoma in Mice

Mantle cell lymphoma (MCL) is a highly aggressive subtype of B-cell lymphoma that is characterized by a poor response to current treatment regimens. Most MCLs carry a prototypical translocation, t(11;14), which juxtaposes the CCND1 gene towards the immunoglobulin heavy chain (IGH) locus, resulting in cyclin D1 overexpression. Strikingly, MCL has not been recapitulated in transgenic mouse models of Ccnd1 overexpression alone. Notably, a subset of MCL patients are cyclin D1 negative but instead overexpress cyclin D2 (encoded by CCND2)as a consequence of recurrent genomic rearrangements involving the CCND2 locus.

Here, we developed a novel conditional ROSA26-driven Ccnd2 overexpression mouse model and showed that hematopoietic-specific Ccnd2 activation is sufficient to drive MCL formation in mice. Starting from 36 weeks, these mice develop huge B-cell lymphomas and these tumor cells have the typical MCL morphology, are Sox11 positive and disseminate into other organs, all typical features of MCL. In addition, preliminary shallow sequencing analysis revealed a somatic Crlf2 deletion as a cooperative genetic event in one of the murine Ccnd2-driven MCL tumors.

In this study, we want to further validate and characterize this novel Ccnd2-driven mouse model for MCL and test putative synergisms between Ccnd2 overexpression and other recurrent cooperating genetic lesions that occur in human MCL, such as loss of p53 or SOX11 activation. Noteworthy, the MCL cells from this mouse model also contain a luciferase reporter, allowing accurate in vivo tracing of tumor cells in xenograft experiments. These xenograft experiments can be used as preclinical models, in which bioluminescence is used to asses the tumor burden and to monitor tumor regression upon drug treatment. In conclusion, we have developed a novel mouse model in which Ccnd2 overexpression faithfully recapitulates MCL and this model will allow us to understand the molecular mechanisms that drive MCL and identify and test novel drugs to treat this aggressive and until now incurable disease.