Diverse marrow stromal cells protect CLL cells from spontaneous and drug-induced apoptosis: development of a reliable and reproducible system to assess stromal cell adhesion-mediated drug resistance
Diverse marrow stromal cells protect CLL cells from spontaneous and drug-induced apoptosis: development of a reliable and reproducible system to assess stromal cell adhesion-mediated drug resistance
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DOI：
10.1182/blood-2009-07-233718
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发表时间：
2009-11-12
期刊：
影响因子：
20.3
通讯作者：
Burger, Jan A.
中科院分区：
文献类型：
--
作者：
Kurtova, Antonina V.;Balakrishnan, Kumudha;Burger, Jan A.
骨髓基质细胞（MSC）为慢性淋巴细胞白血病（CLL）细胞提供重要的存活和耐药性信号，但目前分析CLL-MSC相互作用的模型是异质的。因此，我们测试了不同的人和鼠MSC系和原代人MSC保护CLL细胞免于自发和药物诱导的细胞凋亡的能力。我们的研究结果表明，人类和小鼠骨髓间充质干细胞在保护CLL细胞免受氟达拉滨诱导的细胞凋亡方面同样有效。这种保护作用在广泛的CLL-MSC比例（5：1至100：1）范围内持续存在，并且保护水平在4个不同的实验室中可重现。人和鼠间充质干细胞也保护CLL细胞免受地塞米松和环磷酰胺诱导的凋亡。这种保护需要细胞-细胞接触，并且当CLL细胞通过生物膜过滤器与MSC分离时几乎不存在。此外，MSC维持Mcl-1并保护CLL细胞免于自发和氟达拉滨诱导的Mcl-1和PARP裂解。总的来说，这些研究定义了CLL与MSC共培养的常见促增殖剂。它们还提供了一个可靠的，经过验证的工具，为未来的调查MSC-CLL串扰的机制和药物测试在一个更相关的方式比常用的悬浮培养。（血。2009;114：4441-4450）
Marrow stromal cells (MSCs) provide important survival and drug resistance signals to chronic lymphocytic leukemia (CLL) cells, but current models to analyze CLL-MSC interactions are heterogeneous. Therefore, we tested different human and murine MSC lines and primary human MSCs for their ability to protect CLL cells from spontaneous and drug-induced apoptosis. Our results show that both human and murine MSCs are equally effective in protecting CLL cells from fludarabine-induced apoptosis. This protective effect was sustained over a wide range of CLL-MSC ratios (5:1 to 100:1), and the levels of protection were reproducible in 4 different laboratories. Human and murine MSCs also protected CLL cells from dexamethasone-and cyclophosphamide-induced apoptosis. This protection required cell-cell contact and was virtually absent when CLL cells were separated from the MSCs by micropore filters. Furthermore, MSCs maintained Mcl-1 and protected CLL cells from spontaneous and fludarabine-induced Mcl-1 and PARP cleavage. Collectively, these studies define common denominators for CLL cocultures with MSCs. They also provide a reliable, validated tool for future investigations into the mechanism of MSC-CLL cross talk and for drug testing in a more relevant fashion than the commonly used suspension cultures. (Blood. 2009;114:4441-4450)