Mechanism of gp96/grp94 in regulating plasma cells and myeloma

 描述（由申请方提供）：本研究探讨了grp 94的关键作用，grp 94是浆细胞生物学和多发性骨髓瘤（MM）中内质网（ER）中的一种主要分子伴侣。MM是一种无法治愈的浆细胞肿瘤，其发病机制与ER中未折叠蛋白反应（UPR）失调密切相关。通过转基因表达主UPR转录因子XBP 1 s（X-box结合蛋白1的UPR特异性剪接变体）证明，小鼠中UPR的组成性激活导致骨髓瘤。然而，其潜在机制仍不清楚。我们已经证明grp 94是Wnt共受体低密度脂蛋白受体相关蛋白6（LRP 6）的一种专性伴侣。此外，浆细胞的持久性，以及骨髓瘤在XBP 1 s转基因小鼠的发展是严重依赖于grp 94。骨髓瘤细胞对grp 94的成瘾性也通过使用多发性人骨髓瘤细胞系进行遗传和免疫学证明。此外，我们发现grp 94在MM的恶性浆细胞中高度表达。grp 94的较高水平与MM的更差临床分期显著相关。因此，我们假设MM的发病机制是由UPR和经典Wnt信号转导失调驱动的，两者都会聚在grp 94上。我们将在特定目标1中通过利用我们已经产生的多种独特的遗传工具来解决这一假设，包括B细胞特异性grp 94敲除小鼠和B细胞特异性β-连环蛋白敲除小鼠。在具体目标2中，我们将在新型MM小鼠模型和异种人骨髓瘤模型中确定grp 94在骨髓瘤的全部临床表现中的作用。此外，与Sloan-Kettering癌症研究所的Gabriela Chiosis博士合作，将开发一类新型grp 94特异性抑制剂，并研究其对骨髓瘤的临床前疗效。总体而言，我们的研究不仅将为grp 94在MM发病机制中的作用提供新的基本见解，而且还有助于开发针对这种疾病的grp 94靶向治疗方法。

 DESCRIPTION (provided by applicant): This study addresses the key roles of grp94, a major molecular chaperone in the endoplasmic reticulum (ER) in plasma cell biology and multiple myeloma (MM). MM is an incurable plasma cell neoplasm whose pathogenesis is closely linked to dysregulated unfolded protein response (UPR) in the ER. Constitutive activation of UPR in mice, as demonstrated by transgenic expression of a master UPR transcription factor XBP1s (a UPR-specific splice variant of X-box binding protein 1), causes myeloma. However, the underlying mechanism remains unknown. We have demonstrated that grp94 is an obligate chaperone for Wnt co-receptor low-density lipoprotein receptor-related protein 6 (LRP6). Furthermore, the persistence of plasma cells, as well as the development of myeloma in XBP1s-transgenic mice is critically dependent on grp94. The addiction of myeloma cells to grp94 was also demonstrated genetically and pharmacologically using multiple human myeloma cell lines. Furthermore, we found that grp94 is highly expressed in malignant plasma cells in MM. The higher level of grp94 is significantly associated with a worse clinical stage in MM. Thus, we hypothesize that the pathogenesis of MM is driven by both dysregulated UPR and canonical Wnt signaling, both of which converges onto grp94. We will address this hypothesis in Specific Aim 1, by taking advantage of multiple unique genetic tools we have generated including B cell-specific grp94 knockout mice and B cell-specific β-catenin knockout mice. In Specific Aim 2, we will determine the roles of grp94 in the full clinical manifestation of myeloma in both novel MM mouse models and xenogenic human myeloma model. Moreover, in collaboration with Dr. Gabriela Chiosis from Sloan-Kettering Institute for Cancer Research, a novel class of grp94-specific inhibitors will be developed and investigated for their preclinical efficacy against myeloma. Overall, our studies will not only provide fundamental new insights into the roles of grp94 in the pathogenesis of MM, but also be instrumental in the development of grp94-targeted therapeutics against this disease.