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Blood, 1 October 2008, Vol. 112, No. 7, pp. 2935-2945.
Prepublished online as a Blood First Edition Paper on June 5, 2008; DOI 10.1182/blood-2008-02-142430.
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Submitted February 29, 2008
Accepted May 21, 2008
A unique 3-D model for evaluating the impact of therapy on multiple myeloma
Julia Kirshner, Kyle J. Thulien, Lorri D. Martin, Carina Debes Marun, Tony Reiman, Andrew R Belch, and Linda M Pilarski*
Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada
* Corresponding author; email: lpilarski{at}ualberta.ca.
Although the in vitro expansion of the multiple myeloma (MM) clone has been unsuccessful, in a novel 3-D culture model of reconstructed bone marrow (BM, n=48) and mobilized blood autografts (n=14) presented here, the entire MM clone proliferates and undergoes up to 17-fold expansion of malignant cells harboring the clonotypic IgH VDJ and characteristic chromosomal rearrangements. In this system, MM clone expands in a reconstructed microenvironment that is ideally suited for testing specificity of anti-MM therapeutics. In the 3-D model melphalan and bortezomib had distinct targets, with melphalan targeting the hematopoietic, but not stromal compartment. Bortezomib targeted only CD138+CD56+ MM plasma cells. The localization of non-proliferating cells to the reconstructed endosteum, in contact with N-cadherin positive stroma, suggested the presence of MM-cancer stem cells. These drug-resistant CD20+ cells were enriched >10-fold by melphalan treatment, exhibited self-renewal and generated clonotypic B and plasma cell progeny in colony forming unit assays. This is the first molecularly verified demonstration of proliferation in vitro by ex-vivo MM cells. The 3-D culture provides a novel biologically relevant pre-clinical model for evaluating therapeutic vulnerabilities of all compartments of the MM clone, including presumptive drug-resistant MM stem cell.
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