Characterization of a Novel Mouse Model of Multiple Myeloma and Its Use in Preclinical Therapeutic Assessment

Rosemary A Fryer,Simon P Robinson,Simon Walker-Samuel,Timothy J Graham,Faith E Davies,Emma M Smith,Gareth J Morgan,Maurizio D'Incalci

doi:10.1371/journal.pone.0057641

Rosemary A Fryer, Simon P Robinson + Show 6 more

Open Access

https://doi.org/10.1371/journal.pone.0057641

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Abstract

To aid preclinical development of novel therapeutics for myeloma, an in vivo model which recapitulates the human condition is required. An important feature of such a model is the interaction of myeloma cells with the bone marrow microenvironment, as this interaction modulates tumour activity and protects against drug-induced apoptosis. Therefore NOD/SCIDγcnull mice were injected intra-tibially with luciferase-tagged myeloma cells. Disease progression was monitored by weekly bioluminescent imaging (BLI) and measurement of paraprotein levels. Results were compared with magnetic resonance imaging (MRI) and histology. Assessment of model suitability for preclinical drug testing was investigated using bortezomib, melphalan and two novel agents. Cells engrafted at week 3, with a significant increase in BLI radiance occurring between weeks 5 and 7. This was accompanied by an increase in paraprotein secretion, MRI-derived tumour volume and CD138 positive cells within the bone marrow. Treatment with known anti-myeloma agents or novel agents significantly attenuated the increase in all disease markers. In addition, intra-tibial implantation of primary patient plasma cells resulted in development of myeloma within bone marrow. In conclusion, using both myeloma cell lines and primary patient cells, we have developed a model which recapitulates human myeloma by ensuring the key interaction of tumour cells with the microenvironment.

Highlights

Multiple myeloma is caused by clonal expansion of malignant plasma cells within the bone marrow
An animal model that accurately reflects human myeloma and takes into account the protective nature of bone marrow stromal cells (BMSCs) would be powerful in confirming the efficacy of therapeutic agents in vivo, and accelerate the drug development process
A number of different animal models are currently used to study myeloma, including 5TMM, together with various SCID xenografts, and transgenic models [2,3,4,5,6,7,8,9,10,11]. These models have been useful in highlighting the importance of certain genetic events and signalling pathways in myeloma, they have a number of limitations. These include the use of mouse, rather than human, myeloma cells, a lack of tumour homing and interaction within the bone marrow, the presence of extramedullary disease in the lungs, spleen and liver, and a long latency period before disease establishment

Summary

Introduction

Multiple myeloma is caused by clonal expansion of malignant plasma cells within the bone marrow. Myeloma cells and BMSCs quickly become mutually dependent on one another through a set of feedback loops comprised of various secreted cytokines and growth factors This leads to dysregulation of key processes contributing to enhanced drug resistance. A number of different animal models are currently used to study myeloma, including 5TMM, together with various SCID xenografts, and transgenic models [2,3,4,5,6,7,8,9,10,11] These models have been useful in highlighting the importance of certain genetic events and signalling pathways in myeloma, they have a number of limitations. These include the use of mouse, rather than human, myeloma cells, a lack of tumour homing and interaction within the bone marrow, the presence of extramedullary disease in the lungs, spleen and liver (areas not affected in patients), and a long latency period before disease establishment

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