The Humanized Multiple Myeloma Mouse Model: Opportunities for Studying the Pathogenesis of MM in Its Natural Environment.

Abstract 1847

Poster Board I-873

Multiple myeloma (MM), one of the most common hematological malignancies in adults, is a neoplasm of terminally differentiated B cells, i.e. plasma cells. The transition of a plasma cell to a fully transformed, aggressive myeloma is a multistep process, which requires the acquisition of mutations in multiple genes. Most of this evolution takes place in the bone marrow (BM). Studying the pathogenesis of MM is seriously hampered by the lack of appropriate conditions for the engraftment of patient derived MM cells (pMM) which, unlike MM cell lines, strongly depend on a human microenvironment to engraft, survive and expand, indicating that the interaction of MM cells with the cellular and extracellular components of the human BM microenvironment plays a crucial role in the growth behavior of MM cells. To date only few animal models are described that facilitate the outgrowth of pMM, however, they depend on the co-implantation of human fetal tissues or prior implantation of rabbit bone. Moreover, these do not represent the human adult BM microenvironment in which MM cells normally exist (e.g. in the SCID-Rab model and in the NOD-SCID mouse model) or there are ethical concerns (e.g. the SCID-Hu model).

Here we report the development of a unique mouse model to study the pathobiology of MM by implementing a technology for creating a natural human bone environment in the immune deficient RAG2^−/−γc^−/− 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 RAG2^−/−γc^−/− mice. Within 6 to 8 weeks this leads to the formation of so-called ossicles that contain substantial amounts of human bone, while the remaining open structures are filled with hematopoietic cells (of mouse origin) at various stages of erythroid, megakaryocytic and myeloid differentiation, creating an environment that strongly resembles the human bone marrow. A stricking finding was that this humanized environment in the mouse proved to be capable to not only support human GFP-luciferase gene-marked MM cell lines but also pMM cells. Intravenous or intracardial injection of MM cell lines or pMM cells showed homing to, engraftment and outgrowth of tumor cells in connection with the human bone layer in the ossicles. Hence, this novel humanized mouse model will provide 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 and serve as a model for preclinical testing of new therapeutic approaches for the treatment of Multiple Myeloma patients.