Tracking human multiple myeloma xenografts in NOD-Rag-1/IL-2 receptor gamma chain-null mice with the novel biomarker AKAP-4

Leonardo Mirandola,Yuefei Yu,Constance M John,Everardo Cobos,Maurizio Chiriva-Internati,Marjorie R Jenkins,Raffaella Chiaramonte

doi:10.1186/1471-2407-11-394

Abstract

BackgroundMultiple myeloma (MM) is a fatal malignancy ranking second in prevalence among hematological tumors. Continuous efforts are being made to develop innovative and more effective treatments. The preclinical evaluation of new therapies relies on the use of murine models of the disease.MethodsHere we describe a new MM animal model in NOD-Rag1null IL2rgnull (NRG) mice that supports the engraftment of cell lines and primary MM cells that can be tracked with the tumor antigen, AKAP-4.ResultsHuman MM cell lines, U266 and H929, and primary MM cells were successfully engrafted in NRG mice after intravenous administration, and were found in the bone marrow, blood and spleen of tumor-challenged animals. The AKAP-4 expression pattern was similar to that of known MM markers, such as paraproteins, CD38 and CD45.ConclusionsWe developed for the first time a murine model allowing for the growth of both MM cell lines and primary cells in multifocal sites, thus mimicking the disease seen in patients. Additionally, we validated the use of AKAP-4 antigen to track tumor growth in vivo and to specifically identify MM cells in mouse tissues. We expect that our model will significantly improve the pre-clinical evaluation of new anti-myeloma therapies.

Highlights

Multiple myeloma (MM) is a fatal malignancy ranking second in prevalence among hematological tumors
It has been shown that NOD/SCID mice carrying nonfunctional IL-2 receptor gamma chain (NOD/SCID/gcnull, NOD/ SCID/gcnull (NOG)) are more permissive recipients than NOD/SCID and can be xenografted with human MM cell lines to produce a disease similar to that seen in patients, including multiple metastatic sites and bone lesions [24,25]
IgE was used as a marker for U266 and H929 [38], while primary MM cells were identified by CD38 and CD54 [39]

Summary

Introduction

Multiple myeloma (MM) is a fatal malignancy ranking second in prevalence among hematological tumors. To other malignancies [8], virtually any innovative treatment for MM requires a pre-clinical assessment, which largely relies on the use of animal models to evaluate the anti-tumor potential and possible toxicities [9,10,11,12]. To this goal, sub-lethally irradiated immunodeficient NOD/SCID mice have been extensively used since they allow for human MM cell line xenografting after intravenous injection [13,14,15,16,17,18,19,20,21,22,23]. A further modification of the NOD strain, carrying double genetic disruptions of the Rag and the IL-2 receptor gamma chain genes, namely NOD-Rag1null IL2rgnull (NRG), has been reported to tolerate higher levels of radiation compared with NOD/ SCID and NOG strains and to allow for efficient engraftment of human hematopoietic stem cells [26]

Objectives

Methods

Results

Discussion

Conclusion