Extracellular DNA in regulation of multiple myeloma

摘要 多发性骨髓瘤(MM)是一种毁灭性的骨髓(BM)癌症，一直以来都是致命的 尽管出现了新的治疗方法。肿瘤微环境促进肿瘤 肿瘤间相互作用对肿瘤生长和化疗耐药性的影响 细胞和周围的骨髓细胞。我们的初步数据显示，一群BM 成熟和未成熟的中性粒细胞参与了MM化疗耐药的调节。在……里面 在MM衍生的可溶性因子作用下，中性粒细胞可以释放DNA。这种细胞外无细胞 DNA可能通过激活IRE1/XBP1诱导MM细胞产生化疗耐药 未折叠蛋白反应途径(UPR)。这项提案的目标是确定 MM细胞中无细胞DNA介导的化疗耐药的分子机制 制定一种方法来瞄准它。通过靶向这种新的耐药机制，我们希望 以改善化疗反应，从而改善多发性骨髓瘤的预后。以下是具体的 目标将会得到解决： 具体目的1.明确中性粒细胞释放DNA的机制及临床意义 嗯。 具体目的2.确定无细胞DNA对MM细胞的作用机制。 具体目的3.确定UPR在无细胞DNA介导的MM化疗耐药中的作用。

Abstract Multiple myeloma (MM) is a devastating bone marrow (BM) cancer that remains uniformly fatal despite the emergence of novel therapeutics. The tumor microenvironment promotes tumor growth and resistance to chemotherapy through poorly understood interactions between tumor cells and the surrounding BM cells. Our preliminary data demonstrates that a population of BM mature and immature neutrophils is involved in the regulation of MM chemoresistance. In response to MM-derived soluble factors, neutrophils can release DNA. This extracellular cell-free DNA induces the chemoresistance of MM cells, possibly through activation of IRE1/XBP1 pathway of the unfolded protein response (UPR). The goal of this proposal is to determine the molecular mechanism responsible for cell-free DNA mediated chemoresistance in MM cells and to develop an approach to target it. By targeting of this novel chemoresistance mechanism we hope to improve chemotherapy responses and thereby improve MM outcomes. The following specific aims will be addressed: Specific Aim 1. Identify the mechanisms and clinical relevance of DNA release by neutrophils in MM. Specific Aim 2. Determine the mechanisms of cell-free DNA effect on MM cells. Specific Aim 3. Determine the role of the UPR in cell-free DNA mediated MM chemoresistance.