A unique three-dimensional model for evaluating the impact of therapy on multiple myeloma

克隆(Java方法) 梅尔法兰 间质细胞 骨髓 硼替佐米 多发性骨髓瘤 干细胞 造血 癌症研究 生物 免疫学 细胞生物学 DNA 遗传学
作者
Julia Kirshner,Kyle J. Thulien,L. Martin,Carina Debes Marun,Tony Reiman,Andrew R. Belch,Linda M. Pilarski
出处
期刊:Blood [American Society of Hematology]
卷期号:112 (7): 2935-2945 被引量:110
标识
DOI:10.1182/blood-2008-02-142430
摘要

Abstract Although the in vitro expansion of the multiple myeloma (MM) clone has been unsuccessful, in a novel three-dimensional (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 com-partment. Bortezomib targeted only CD138+CD56+ MM plasma cells. The localization of nonproliferating 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 more than 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 preclinical model for evaluating therapeutic vulnerabilities of all compartments of the MM clone, including presumptive drug-resistant MM stem cells.
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