Section of Molecular Hematology and Therapy, Department of Leukemia.
Blood. 2014 Apr 24;123(17):2691-702. doi: 10.1182/blood-2013-06-511527. Epub 2014 Mar 5.
Leukemia cells are protected from chemotherapy-induced apoptosis by their interactions with bone marrow mesenchymal stromal cells (BM-MSCs). Yet the underlying mechanisms associated with this protective effect remain unclear. Genome-wide gene expression profiling of BM-MSCs revealed that coculture with leukemia cells upregulated the transcription of genes associated with nuclear factor (NF)-κB signaling. Moreover, primary BM-MSCs from leukemia patients expressed NF-κB target genes at higher levels than their normal BM-MSC counterparts. The blockade of NF-κB activation via chemical agents or the overexpression of the mutant form of inhibitor κB-α (IκBα) in BM-MSCs markedly reduced the stromal-mediated drug resistance in leukemia cells in vitro and in vivo. In particular, our unique in vivo model of human leukemia BM microenvironment illustrated a direct link between NF-κB activation and stromal-associated chemoprotection. Mechanistic in vitro studies revealed that the interaction between vascular cell adhesion molecule 1 (VCAM-1) and very late antigen-4 (VLA-4) played an integral role in the activation of NF-κB in the stromal and tumor cell compartments. Together, these results suggest that reciprocal NF-κB activation in BM-MSCs and leukemia cells is essential for promoting chemoresistance in the transformed cells, and targeting NF-κB or VLA-4/VCAM-1 signaling could be a clinically relevant mechanism to overcome stroma-mediated chemoresistance in BM-resident leukemia cells.
白血病细胞通过与骨髓间充质基质细胞（BM-MSCs）相互作用而免受化疗诱导的细胞凋亡。然而，与这种保护作用相关的潜在机制尚不清楚。对 BM-MSCs 的全基因组基因表达谱分析显示，与白血病细胞共培养会上调与核因子（NF）-κB 信号相关的基因转录。此外，白血病患者的原代 BM-MSCs 表达 NF-κB 靶基因的水平高于其正常 BM-MSC 对应物。通过化学试剂阻断 NF-κB 激活或在 BM-MSCs 中过表达突变型 IκBα（IκBα）可显著降低白血病细胞在体外和体内的基质介导的耐药性。特别是，我们独特的人白血病 BM 微环境体内模型表明 NF-κB 激活与基质相关的化学保护之间存在直接联系。体外机制研究表明，血管细胞黏附分子 1（VCAM-1）和非常晚期抗原 4（VLA-4）之间的相互作用在基质和肿瘤细胞区室中 NF-κB 的激活中起着重要作用。总之，这些结果表明，BM-MSCs 和白血病细胞中相互的 NF-κB 激活对于促进转化细胞的化疗耐药性是必不可少的，并且靶向 NF-κB 或 VLA-4/VCAM-1 信号可能是克服 BM 驻留白血病细胞中基质介导的化疗耐药性的一种临床相关机制。
