Lehners Nicola, Ellert Elena, Xu Jing, Hillengass Jens, Leichsenring Jonas, Stenzinger Albrecht, Goldschmidt Hartmut, Andrulis Mindaugas, Raab Marc S
a Department of Internal Medicine V , University Hospital Heidelberg , Heidelberg , Germany.
b Max-Eder-Group Experimental Therapies for Hematologic Malignancies , German Cancer Research Center (DKFZ) and University Hospital Heidelberg , Heidelberg , Germany.
Leuk Lymphoma. 2018 Nov;59(11):2660-2669. doi: 10.1080/10428194.2018.1443450. Epub 2018 Apr 4.
Oncogene-induced senescence (OIS) is a cellular tumor-suppressive mechanism present in several premalignant conditions. Here, we analyze the possible impact of OIS on malignant transformation in plasma cell disorders. Tumor samples from 125 patients with different disease stages were analyzed immunohistochemically for expression of senescence markers. Protein expression of cyclin-dependent kinase inhibitor p21 was significantly higher in smoldering multiple myeloma (SMM) compared to monoclonal gammopathy of undetermined significance (MGUS) (p = .02) or symptomatic multiple myeloma (MM) (p = .005). SMM plasma cells expressing p21 were negative for Ki67, consistent with senescence. While p27 was highly expressed in healthy controls, MGUS and SMM, expression decreased significantly in MM (p = .02). SMM plasma cells displayed a mutually exclusive expression of p21/p27 suggesting compensatory mechanisms of senescence. In conclusion, we found markers of cellular senescence differentially expressed in SMM compared to MGUS and MM supporting the hypothesis of OIS as a breakpoint mechanism against malignant transformation in plasma cell disorders.
癌基因诱导的衰老（OIS）是一种存在于多种癌前病变中的细胞肿瘤抑制机制。在此，我们分析了OIS对浆细胞疾病恶性转化的可能影响。对125例不同疾病阶段患者的肿瘤样本进行免疫组织化学分析，以检测衰老标志物的表达。与意义未明的单克隆丙种球蛋白病（MGUS）（p = 0.02）或有症状的多发性骨髓瘤（MM）（p = 0.005）相比，冒烟型多发性骨髓瘤（SMM）中细胞周期蛋白依赖性激酶抑制剂p21的蛋白表达显著更高。表达p21的SMM浆细胞Ki67呈阴性，与衰老一致。虽然p27在健康对照、MGUS和SMM中高表达，但在MM中表达显著降低（p = 0.02）。SMM浆细胞显示p21/p27相互排斥的表达，提示衰老的补偿机制。总之，我们发现与MGUS和MM相比，SMM中细胞衰老标志物存在差异表达，支持OIS作为浆细胞疾病恶性转化断点机制的假说。
