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]
日期:2008-10-01
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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