Haematology Consulting RooLiverpool Hospital, Locked Bag 7090, Liverpool BC NSW 1871, Australia.
Haematologica. 2012 Jan;97(1):64-72. doi: 10.3324/haematol.2011.043331. Epub 2011 Oct 11.
Multiple myeloma, a malignancy of the antibody-secreting plasma cells, remains incurable by current therapy. However, the proteasome inhibitor bortezomib and other new drugs are revolutionizing its treatment. It remains unclear why myelomas are peculiarly sensitive to bortezomib, or what causes primary or acquired resistance. The 'unfolded protein response' is necessary for folding and assembly of immunoglobulin chains in both normal and malignant plasma cells, as well as for the disposal of incorrectly folded or unpaired chains via the ubiquitin-proteasome pathway. We tested the hypothesis that levels of transcription factor XBP-1, a major regulator of the unfolded protein response, predict response to bortezomib.
Expression of XBP-1 and other regulators of the unfolded protein response were measured in myeloma and other cancer cell lines and two cohorts of patients with refractory myeloma and correlated with sensitivity/response to bortezomib. Bortezomib-resistant myeloma cell lines were derived and the effects on expression of unfolded protein response regulators, immunoglobulin secretion, proteasome activity and cross-resistance to cytotoxic drugs and tunicamycin determined. The consequences of manipulation of XBP-1 levels for sensitivity to bortezomib were tested.
Low XBP-1 levels predicted poor response to bortezomib, both in vitro and in myeloma patients. Moreover, myeloma cell lines selected for resistance to bortezomib had down-regulated XBP-1 and immunoglobulin secretion. Expression of ATF6, another regulator of the unfolded protein response, also correlated with bortezomib sensitivity. Direct manipulation of XBP-1 levels had only modest effects on sensitivity to bortezomib, suggesting it is a surrogate marker of response to bortezomib rather than a target itself.
The unfolded protein response may be a relevant target pathway for proteasome inhibitors in the treatment of myeloma and its regulator XBP-1 is a potential response marker. (The BIR study was registered with Australian Clinical Trial Registry Number 12605000770662).
多发性骨髓瘤是一种由抗体分泌浆细胞引起的恶性肿瘤，目前的治疗方法仍无法治愈。然而，蛋白酶体抑制剂硼替佐米和其他新药正在彻底改变其治疗方法。目前尚不清楚为什么多发性骨髓瘤对硼替佐米特别敏感，或者是什么导致了原发性或获得性耐药。 unfolded protein response（未折叠蛋白反应）对于正常和恶性浆细胞中免疫球蛋白链的折叠和组装，以及通过泛素-蛋白酶体途径处理错误折叠或未配对的链都是必要的。我们测试了这样一个假设，即转录因子 XBP-1 的水平， unfolded protein response 的主要调节因子，可预测对硼替佐米的反应。
在骨髓瘤和其他癌细胞系中测量 XBP-1 和 unfolded protein response 的其他调节剂的表达，并将其与硼替佐米的敏感性/反应相关联。衍生出硼替佐米耐药的骨髓瘤细胞系，并确定其对 unfolded protein response 调节剂的表达、免疫球蛋白分泌、蛋白酶体活性以及对细胞毒性药物和衣霉素的交叉耐药性的影响。测试了操纵 XBP-1 水平对硼替佐米敏感性的影响。
低 XBP-1 水平预测了硼替佐米在体外和骨髓瘤患者中的不良反应。此外，对硼替佐米耐药的骨髓瘤细胞系下调了 XBP-1 和免疫球蛋白分泌。 unfolded protein response 的另一个调节剂 ATF6 的表达也与硼替佐米的敏感性相关。直接操纵 XBP-1 水平对硼替佐米的敏感性仅有适度影响，这表明它是硼替佐米反应的替代标志物，而不是自身的靶点。
unfolded protein response 可能是蛋白酶体抑制剂治疗骨髓瘤的相关靶点途径，其调节剂 XBP-1 是一个潜在的反应标志物。（BIR 研究在澳大利亚临床试验注册中心注册，编号为 12605000770662）。
