A Clinically Relevant SCID-hu in Vivo Model of Human Multiple Myeloma.

Abstract

Human multiple myeloma (MM) xenografts in immunodeficient mice have limitations as a model for the human disease since they lack the human bone marrow (huBM) microenvironment. In contrast, murine models harboring a huBM microenvironment with implantation of patient MM cells in the huBM recapitulate the in vivo pathophysiology of MM and have significant advantages over conventional murine models for pre-clinical evaluation of investigational drugs. However, there are significant limitations in using patient MM cells in such models since i) not all patient MM samples engraft in the huBM; ii) only a fraction of engrafted specimens produce measurable paraprotein and/or osteolytic lesions; and iii) a limited number of MM cells can be harvested from an individual patient, thus limiting the number of mice that can be injected with cells from the same patient. To overcome these limitations, we have developed a novel murine model of MM by engrafting INA-6, a cytokine-dependent human MM cell line into SCID mice previously implanted with a human fetal bone chip (SCID-hu mice). INA-6 cells require either exogenous IL-6 or interaction with the bone marrow stromal cells (BMSCs) to proliferate in vitro. In this model, we monitored the in vivo growth of INA-6 cells stably transfected with a green fluorescent protein (GFP) expression vector (INA-6GFP+). Serum soluble human IL-6 receptor (shuIL-6R) and fluorescence imaging of host animals were sensitive indicators of tumor burden with time dependent increase. Fluorescence imaging was able to detect the myeloma cell growth earlier than measurement of sIL-6R levels. INA-6 MM cells grew in SCID-hu mice, but not in SCID mice injected subcutaneously or intravenously without the human fetal bone. We have further confirmed the feasibility of this model in monitoring the response to therapeutic agents such as dexamethasone by detecting reduction in the intensity of the fluorescent lesions as well as shuIL-6R in SCID-hu mice following anti-MM treatment. This highly reproducible model therefore allows for evaluation of investigational drugs targeting MM cells in the huBM milieu.

p38 mitogen‐activated protein kinase inhibitor LY2228820 enhances bortezomib‐induced cytotoxicity and inhibits osteoclastogenesis in multiple myeloma; therapeutic implications

“…To evaluate the in vivo effect of LY treatment on MM cells and osteoclastogenesis in a human BM microenviornment, we used the SCID‐hu murine model of human MM (Tassone et al , 2005). This model allows for the growth of human MM cells in a human BM microenvironment, allowing for evaluation of human osteoclastogenesis in a fetal bone chip in the presence of human MM cells.…”

“…The humanized severe combined immunodeficiency (SCID‐hu) INA‐6 mouse model was used as previously described (Tassone et al , 2004, 2005). Six mice developed detectable serum shuIL‐6R levels approximately 4 weeks following INA‐6 cell injection into bone chip, and three mice were then treated three times daily with either 44 mg/kg LY or vehicle orally for 21 consecutive days, respectively.…”

Serum B‐cell maturation antigen is elevated in multiple myeloma and correlates with disease status and survival

“…However, these markers are not produced directly by MM cells. IL‐6 and its soluble receptor have been used to follow human MM growth in mice (Tassone et al , ). However, assessment of these proteins to follow MM patients has proven less useful, probably due to their widespread presence in many other cell types (Jones et al , ).…”

The selective adhesion molecule inhibitor Natalizumab decreases multiple myeloma cell growth in the bone marrow microenvironment: therapeutic implications

“…Based on these in vitro data, we next evaluated the anti-MM activity of Natalizumab in our SCID-hu murine model of MM (Tassone et al, 2005). In this model, a subcutaneously implanted fetal human bone chip is engrafted with MM INA-6 cells (Burger et al, 2001), reflecting human MM in the human BM milieu.…”