Billadeau D, Jelinek D F, Shah N, LeBien T W, Van Ness B
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis 55455, USA.
Cancer Res. 1995 Aug 15;55(16):3640-6.
Multiple myeloma (MM) is a late-stage B-cell cancer with an unknown etiology. Activating mutations of the N-ras and K-ras oncogenes occur with a high frequency in myeloma and, therefore, may play a role in the pathogenesis of the disease. To study the role of N-ras-activating mutations in the regulation of myeloma tumor growth, we introduced a constitutively active N-ras cDNA containing a glutamine to arginine (CAA-CGA) amino acid substitution at codon 61 into the interleukin 6 (IL-6)-dependent myeloma cell line ANBL6. Expression of the mutant N-ras cDNA resulted in significant IL-6-independent growth, as well as augmentation of growth at suboptimal concentrations of IL-6. The IL-6-independent growth pattern was not the result of activation of autocrine IL-6 production in the mutant N-ras-expressing population because neutralizing antibodies to the IL-6 receptor and to IL-6 had no effect on the rate of DNA synthesis in the absence of IL-6. Furthermore, mutant N-ras expression decreased the percentage of cells undergoing apoptosis in the absence of IL-6. These data suggest that activating mutations of the ras oncogenes may result in growth factor independence accompanied by a suppression of apoptosis in MM. Therefore, the use of therapies designed to block IL-6 action in MM may have less of an impact on tumors bearing activated ras mutations.
多发性骨髓瘤（MM）是一种病因不明的晚期B细胞癌。N-ras和K-ras癌基因的激活突变在骨髓瘤中高频发生，因此可能在该疾病的发病机制中起作用。为了研究N-ras激活突变在骨髓瘤肿瘤生长调节中的作用，我们将一个在第61位密码子处含有谷氨酰胺到精氨酸（CAA-CGA）氨基酸替换的组成型活性N-ras cDNA导入白细胞介素6（IL-6）依赖的骨髓瘤细胞系ANBL6中。突变型N-ras cDNA的表达导致显著的IL-6非依赖性生长，以及在次优浓度的IL-6下生长增强。IL-6非依赖性生长模式不是突变型N-ras表达群体中自分泌IL-6产生激活的结果，因为针对IL-6受体和IL-6的中和抗体在没有IL-6的情况下对DNA合成速率没有影响。此外，突变型N-ras表达降低了在没有IL-6的情况下经历凋亡的细胞百分比。这些数据表明，ras癌基因的激活突变可能导致生长因子非依赖性，并伴有MM中凋亡的抑制。因此，在MM中使用旨在阻断IL-6作用的疗法可能对携带激活ras突变的肿瘤影响较小。
