A Unique New Humanized Mouse Model for Multiple Myeloma (MM): Opportunities for Studying MM In Its Natural Environment and for Preclinical Testing

Abstract

AbstractAbstract 981Here we report the development of a unique mouse model to study the pathobiology of multiple myeloma (MM) by implementing a technology for creating a natural human bone environment in the immune deficient RAG2γ-/-c-/- mouse. To this end we combined a procedure to culture-expand human BM-derived mesenchymal stromal cells (MSC) that were seeded on biphasic calcium phosphate (BCP) particles and subsequently implanted subcutaneously in RAG2γ-/-c-/- mice. Within 6 weeks this leads to the formation of so-called ossicles that contain substantial amounts of human bone, while the remaining open spaces are filled with mouse hematopoietic cells and blood vessels, creating an environment that strongly resembles the human bone marrow. A striking finding was that this humanized environment in the mouse acts as a 3-D natural “niche” for patient MM (pMM) cells. Intrascaffold injection of pMM cells resulted in engraftment and outgrowth of tumor cells in close contact with the human bone layer in the ossicles. In addition, intracardial injection, revealed that these primary tumor cells were also capable of homing to the implanted artificial BM-niches, while no tumor cells were detected in the mouse BM. The outgrowth of pMM in this model is accompanied by an increase in osteoclast number on the bone surface, indicating the presence of bone resorption, one of the most important clinical sequelae of MM. Interestingly, by gene-marking pMM cells with luciferase and using bioluminescent imaging, we were able to follow myeloma outgrowth in time, and visualize the effect of treatment. Hence, this novel humanized mouse model provides the first opportunity to investigate patient-derived MM plasma cells in their natural environment, which may lead to better insights in the pathogenesis of this disease. Furthermore, it could serve as a model for preclinical testing of new therapeutic approaches for the treatment of MM patients. Disclosures:de Weers:Genmab bv: Employment.