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

项目概要/摘要 沙利度胺（塔尔）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（IMiD）和其他一些药物 血液恶性肿瘤虽然它们代表了两种新的 诊断和复发/难治性MM患者，其临床使用仍然主要是经验性的， 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结合结构域中的不同氨基酸序列， cereblon（CRBN）。通过建立我们广泛验证的Vk*MYC转基因小鼠模型， MM，我们已经产生了一种新的转基因小鼠，Vk*MYChCRBN，表达完整的人CRBN， （hCRBN）基因在其内源性调控元件的控制下，使其对IMiD敏感。 正如之前对Vk*MYC模型所做的那样，我们将广泛表征新的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.