Department of Biochemistry & Molecular Biology, College of Medicine, Mayo Clinic Arizona, Scottsdale, AZ 85259, USA.
Division of Hematology, Mayo Clinic Arizona, Scottsdale, AZ 85259, USA.
Int J Mol Sci. 2017 Sep 17;18(9):1999. doi: 10.3390/ijms18091999.
Immunomodulatory drugs (IMiDs) are profoundly active compounds in the treatment of patients with multiple myeloma (MM). However, despite the fact that treatment with IMiDs has dramatically improved survival for patients with MM, the majority of MM patients develop IMiDs resistance over time. We have found that expression of functional cereblon is required for IMiDs' action. In addition, it has been reported that cells expressing high levels of cereblon are resistant to proteasome inhibitor, implying that patients with high levels of cereblon should be resistant to proteasome inhibitor. If the above conclusions are correct, cereblon could be considered as a biomarker to determine which standard regimens should be used to treat patients with MM. Unfortunately, the conclusions mentioned above have not been clinically confirmed. In order to confirm these conclusions, we have generated three highly specific mouse monoclonal antibodies (mAbs) against full-length human cereblon. These mAbs can be used to do western blot, immunoprecipitation and immunohistochemistry staining. In addition, their epitopes have been precisely determined and the peptides covering their epitopes completely blocked the antibody binding to cereblon in western blot analysis or in immunohistochemistry staining of MM patients' specimens.
免疫调节药物（IMiDs）在治疗多发性骨髓瘤（MM）患者方面具有显著的活性。然而，尽管 IMiDs 的治疗极大地改善了 MM 患者的生存，但大多数 MM 患者随着时间的推移会产生 IMiDs 耐药性。我们发现功能性 cereblon 的表达是 IMiDs 作用所必需的。此外，据报道，表达高水平 cereblon 的细胞对蛋白酶体抑制剂具有耐药性，这意味着 cereblon 水平高的患者应该对蛋白酶体抑制剂具有耐药性。如果上述结论是正确的，cereblon 可以被认为是一个生物标志物，以确定哪些标准方案应该用于治疗 MM 患者。不幸的是，上述结论尚未在临床上得到证实。为了证实这些结论，我们生成了三种针对全长人 cereblon 的高度特异性小鼠单克隆抗体（mAbs）。这些 mAbs 可用于进行 Western blot、免疫沉淀和免疫组织化学染色。此外，它们的表位已被精确确定，并且包含其表位的肽在 Western blot 分析或 MM 患者标本的免疫组织化学染色中完全阻断了抗体与 cereblon 的结合。
