Abstract 1346: Induction of multiple myeloma in a novel humanized bone marrow xenograft model does not depend on CD138 expression

Abstract

Abstract Multiple myeloma (MM) is an incurable B lineage malignancy characterized by an accumulation of monoclonal plasma cells in the bone marrow (BM) and is responsible for 20% of deaths from hematological cancers. MM patients present with an overproduction of monoclonal immunoglobulin, anemia, and hypercalcemia resulting in susceptibility to infection and end organ damage. Patients develop lytic bone lesions resulting in pathological fractures and significant pain. Plasmacytomas, solid tumors comprised of a single plasma cell clone, and extramedullary MM, presenting with lesions in the liver, lungs, and other organs, have also been reported in patients. Despite the development of potent new therapies, the median survival of MM patients remains 3-5 years, suggesting that a drug-resistant cancer stem cell (CSC) may be responsible for the inevitable relapse. We developed a clinically relevant humanized BM murine model of MM utilizing the NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mouse line (huBM/NSG model), sensitive enough to study the behavior of the putative CSC populations. To recapitulate the clinical symptoms of MM varying MM cell lines and primary cells from BM biopsies were co-transplanted with human BM stromal cells via an intratibial injection. Upon engraftment (5-15 weeks), mice developed systemic MM, plasmacytoma, and extramedullary disease. huBM/NSG mice developed symptoms of MM, including lytic bone lesions, elevated serum calcium, and low hemoglobin, mimicking the human presentation of MM with bone lesions, hypercalcemia, and anemia. In contrast to MM cell lines that induced disease without the support of human BM stroma, primary MM cells were able to engraft mouse bones and cause disease only when co-injected with human BM stromal cells. To determine whether CD138 can be used as a reliable marker for the MM-CSC, MM cells were sorted into CD138 positive and negative populations and injected into huBM/NSG mice to determine engraftment efficiency of each fraction. Surprisingly, both CD138+ and CD138- cell populations were able to engraft MM in huBM/NSG mice in primary and secondary transplants. Thus, it appears that CD138 expression is irrelevant for the engraftment of MM cells and subsequent initiation of the disease, suggesting that the MM-CSCs are present in both CD138+ and CD138- fractions. Taken together our study presents a new in vivo model of MM where the human BM microenvironment is reconstructed in the mouse faithfully recapitulating MM as it presents in human patients. We further establish that human stromal support is essential for the engraftment of primary MM cells, historically a challenging process. Furthermore, our data support the emerging findings that CD138 is not a reliable marker of the MM-CSCs, suggesting that the previously demonstrated differential engraftment of selected populations is likely an artifact of the less sensitive animal models. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1346. doi:1538-7445.AM2012-1346