Annunziata Christina M, Davis R Eric, Demchenko Yulia, Bellamy William, Gabrea Ana, Zhan Fenghuang, Lenz Georg, Hanamura Ichiro, Wright George, Xiao Wenming, Dave Sandeep, Hurt Elaine M, Tan Bruce, Zhao Hong, Stephens Owen, Santra Madhumita, Williams David R, Dang Lenny, Barlogie Bart, Shaughnessy John D, Kuehl W Michael, Staudt Louis M
Metabolism Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Cancer Cell. 2007 Aug;12(2):115-30. doi: 10.1016/j.ccr.2007.07.004.
Mechanisms of constitutive NF-kappaB signaling in multiple myeloma are unknown. An inhibitor of IkappaB kinase beta (IKKbeta) targeting the classical NF-kappaB pathway was lethal to many myeloma cell lines. Several cell lines had elevated expression of NIK due to genomic alterations or protein stabilization, while others had inactivating mutations of TRAF3; both kinds of abnormality triggered the classical and alternative NF-kappaB pathways. A majority of primary myeloma patient samples and cell lines had elevated NF-kappaB target gene expression, often associated with genetic or epigenetic alteration of NIK, TRAF3, CYLD, BIRC2/BIRC3, CD40, NFKB1, or NFKB2. These data demonstrate that addiction to the NF-kappaB pathway is frequent in myeloma and suggest that IKKbeta inhibitors hold promise for the treatment of this disease.
多发性骨髓瘤中组成型NF-κB信号传导的机制尚不清楚。一种靶向经典NF-κB途径的IkappaB激酶β（IKKβ）抑制剂对许多骨髓瘤细胞系具有致死性。由于基因组改变或蛋白质稳定，几种细胞系中NIK表达升高，而其他细胞系则具有TRAF3的失活突变；这两种异常均触发经典和替代NF-κB途径。大多数原发性骨髓瘤患者样本和细胞系中NF-κB靶基因表达升高，这通常与NIK、TRAF3、CYLD、BIRC2/BIRC3、CD40、NFKB1或NFKB2的遗传或表观遗传改变有关。这些数据表明，骨髓瘤中对NF-κB途径的依赖很常见，并提示IKKβ抑制剂有望用于治疗这种疾病。
