A Transgenic mouse model of plasma cell malignancy shows phenotypic, cytogenetic, and gene expression heterogeneity similar to human multiple myeloma
A Transgenic mouse model of plasma cell malignancy shows phenotypic, cytogenetic, and gene expression heterogeneity similar to human multiple myeloma
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DOI：
10.1158/0008-5472.can-06-3699
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发表时间：
2007-05-01
期刊：
影响因子：
11.2
通讯作者：
Van Ness, Brian G.
中科院分区：
文献类型：
--
作者：
Boylan, Kristin L. M.;Gosse, Mary A.;Van Ness, Brian G.
多发性骨髓瘤是一种无法治愈的浆细胞恶性肿瘤，现有的动物模型有限。我们先前已经表明，在鼠浆细胞中靶向表达转基因c-Myc和Bcl-X-L产生恶性肿瘤，其显示人类骨髓瘤的特征，例如肿瘤细胞定位于骨髓和溶解性骨病变。我们已经从Bcl-xl/Myc转基因小鼠中分离并鉴定了肿瘤的体外培养和过继转移。肿瘤具有浆母细胞形态和可变的CD 138、CD 45、CD 38和CD 19表达。对原代肿瘤细胞培养物的中期染色体进行光谱核型分析表明，Bcl-xl/Myc肿瘤含有多种染色体异常，包括三体、易位和缺失。最常见的异常染色体是12和16。在染色体41、12 F和16 C上也发现了三个重复易位位点。基因表达谱用于鉴定肿瘤细胞和正常浆细胞（NPC）之间的基因表达差异，并将肿瘤聚类为具有不同基因表达谱的两组（肿瘤组C和D）。495个基因在肿瘤组和NPC之间存在显著差异，而124个基因在肿瘤组C中与NPC独特不同，204个基因在肿瘤组D中与NPC独特不同。与人骨髓瘤相似，小鼠肿瘤组中细胞周期蛋白D基因差异失调。这些数据表明，Bcl-xl/Myc肿瘤类似于浆细胞瘤人类骨髓瘤的一个子集，并提供了对人类疾病潜在的特定基因和途径的深入了解。
Multiple myeloma is an incurable plasma cell malignancy for which existing animal models are limited. We have previously shown that the targeted expression of the transgenes c-Myc and Bcl-X-L in murine plasma cells produces malignancy that displays features of human myeloma, such as localization of tumor cells to the bone marrow and lytic bone lesions. We have isolated and characterized in vitro cultures and adoptive transfers of tumors from Bcl-xl/Myc transgenic mice. Tumors have a plasmablastic morphology and variable expression of CD138, CD45, CD38, and CD19. Spectral karyotyping analysis of metaphase chromosomes from primary tumor cell cultures shows that the Bcl-xl/Myc tumors contain a variety of chromosomal abnormalities, including trisomies, translocations, and deletions. The most frequently aberrant chromosomes are 12 and 16. Three sites for recurring translocations were also identified on chromosomes 41), 12F, and 16C. Gene expression profiling was used to identify differences in gene expression between tumor cells and normal plasma cells (NPC) and to cluster the tumors into two groups (tumor groups C and D), with distinct gene expression profiles. Four hundred and ninety-five genes were significantly different between both tumor groups and NPCs, whereas 124 genes were uniquely different from NPCs in tumor group C and 204 genes were uniquely different from NPCs in tumor group D. Similar to human myeloma, the cyclin D genes are differentially dysregulated in the mouse tumor groups. These data suggest the Bcl-xl/Myc tumors are similar to a subset of plasmablastic human myelomas and provide insight into the specific genes and pathways underlying the human disease.