Credentialing a Genetically Engineered Clinically-Relevant Mouse Model of Multiple Myeloma

项目摘要/摘要 沙利度胺(THAL)及其衍生物来那度胺(LEN)和泊马度胺(POM)是免疫的 用于治疗多发性骨髓瘤(MM)的调节药物(IMids)等 恶性血液病。尽管它们代表着治疗这两种新疾病的骨干 确诊和复发/难治性多发性骨髓瘤患者，他们的临床应用大多仍是经验性的，因为 缺乏合适的体内模型系统来研究其复杂的作用机制。小鼠细胞是 由于IMiD结合区的氨基酸序列不同而对IMiDS产生固有抗性 克雷布隆(CRBN)。通过构建我们广泛验证的VK*MYC转基因小鼠模型 嗯，我们培育了一种新型的转基因小鼠VK*MYChCRBN，表达了完整的人CRBN (HCRBN)基因受其内源性调控元件的控制，使其对IMIDD敏感。 正如之前针对VK*MYC模型所做的那样，我们将广泛描述新的VK*MYChCRBN 模型，并将使用它来了解IMiD对肿瘤和免疫系统的影响 最终目标是为临床实践提供信息。

Project Summary/Abstract Thalidomide (Thal) and its derivatives, Lenalidomide (Len) and Pomalidomide (POM), are immune modulatory drugs (IMiDs) used in the treatment of multiple myeloma (MM) and few other hematological malignancies. Although they represent the backbone treatment for both newly diagnosed and relapse/refractory MM patients, their clinical use remains mostly empirical because of lack of suitable in vivo model systems to study their complex mechanisms of action. Murine cells are intrinsically resistant to IMiDs because of different amino acid sequence in the IMiD binding domain of cereblon (CRBN). By building upon our extensively validated Vk*MYC transgenic mouse model of MM, we have generated a novel transgenic mouse, Vk*MYChCRBN, expressing the full human CRBN (hCRBN) gene under the control of its endogenous regulatory elements, rendering it IMiD sensitive. As previously done for the Vk*MYC model, we will extensively characterize the new Vk*MYChCRBN model and will use it to understand the IMiD effects on the tumor and the immune system with the ultimate goal to inform clinical practice.