Abstract
Animal models of multiple myeloma vary in terms of consistency of onset, degree of tumour burden and degree of myeloma bone disease. Here we describe five pre-clinical models of myeloma in NOD/SCID-GAMMA mice to specifically study the effects of therapeutic agents on myeloma bone disease. Groups of 7–8 week old female irradiated NOD/SCID-GAMMA mice were injected intravenously via the tail vein with either 1x106 JJN3, U266, XG-1 or OPM-2 human myeloma cell lines or patient-derived myeloma cells. At the first signs of morbidity in each tumour group all animals were sacrificed. Tumour load was measured by histological analysis, and bone disease was assessed by micro-CT and standard histomorphometric methods. Mice injected with JJN3, U266 or OPM-2 cells showed high tumour bone marrow infiltration of the long bones with low variability, resulting in osteolytic lesions. In contrast, mice injected with XG-1 or patient-derived myeloma cells showed lower tumour bone marrow infiltration and less bone disease with high variability. Injection of JJN3 cells into NOD/SCID-GAMMA mice resulted in an aggressive, short-term model of myeloma with mice exhibiting signs of morbidity 3 weeks later. Treating these mice with zoledronic acid at the time of tumour cell injection or once tumour was established prevented JJN3-induced bone disease but did not reduce tumour burden, whereas, carfilzomib treatment given once tumour was established significantly reduced tumour burden. Injection of U266, XG-1, OPM-2 and patient-derived myeloma cells resulted in less aggressive longer-term models of myeloma with mice exhibiting signs of morbidity 8 weeks later. Treating U266-induced disease with zoledronic acid prevented the formation of osteolytic lesions and trabecular bone loss as well as reducing tumour burden whereas, carfilzomib treatment only reduced tumour burden. In summary, JJN3, U266 or OPM-2 cells injected into NOD/SCID-GAMMA mice provide robust models to study anti-myeloma therapies, particularly those targeting myeloma bone disease.
Highlights
Multiple myeloma (MM) is a cancer of differentiated B-lymphocytes leading to the clonal expansion of plasma cells in the bone marrow (BM)
We have determined the time to onset of disease, the variability in tumour burden and the extent of bone disease in NSG mice injected with 4 different myeloma cell lines and patient-derived cells compared to non-tumour control mice
Injection of JJN3, U266 or OPM-2 cells into NSG mice results in high tumour burden and severe bone disease with low variability in tumour burden, whereas injection of XG-1 and patient-derived cells results in lower bone marrow infiltration and bone disease with higher variability
Summary
Multiple myeloma (MM) is a cancer of differentiated B-lymphocytes leading to the clonal expansion of plasma cells in the bone marrow (BM). A number of pre-clinical animal models of MM have been developed to assess the efficacy of therapeutic agents used in the treatment of myeloma bone disease (MBD) [1,2,3,4,5,6,7]. Most recently the immune-suppressed NOD/SCID-GAMMA (NSG) strain of mice has been used successfully in human xenograft models of MM. In these studies, a number of myeloma cell lines [8,9,10,11,12] and patient-derived myeloma cells [10,11,12] were injected into NSG mice leading to varying levels of BM infiltration. Further investigation is required to identify and validate the best models in terms of consistency of onset, degree of tumour infiltration and extent of MBD
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