Role of MIF in myeloma bone homing and drug response

MIF 在骨髓瘤骨归巢和药物反应中的作用

• 批准号: 9211149
• 负责人: Qing Yi
• 金额: $ 36.26万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9211149
• 关键词: Adhesions; Affect; Affinity; Apoptosis; Bone Marrow; Bone Pain; Cancer Etiology; Cell Line; Cells; Databases; Development; Disease; Disease Management; Drug resistance; Extramedullary; Future; Gene Expression Profiling; Growth; Homing; Human; Hypercalcemia; Impairment; In Vitro; Injection of therapeutic agent; Intravenous; Lead; Malignant - descriptor; Malignant Bone Neoplasm; Malignant Neoplasms; Mediating; Metastatic Neoplasm to the Bone; Migration Inhibitory Factor; Multi-Drug Resistance; Multiple Myeloma; Nature; Pathogenesis; Pathological fracture; Patients; Pharmaceutical Preparations; Plasma Cells; Publishing; Reagent; Recruitment Activity; Relapse; Resistance; Role; SCID Mice; SCID-hu Mice; Stromal Cells; Testing; Treatment Efficacy; Treatment Failure; Tumor Burden; United States; advanced disease; base; bone; bone cell; cancer cell; chemokine; chemotherapy; clinical application; conditioning; effective therapy; experience; improved; inhibitor/antagonist; knock-down; macrophage; monocyte; neoplastic cell; neutralizing monoclonal antibodies; novel; phenylpyruvate tautomerase; response; tool; tumor

Project Summary Multiple myeloma (MM), characterized by an accumulation of malignant plasma cells in the bone marrow (BM), is the most common bone malignancy in the United States. Although chemotherapy is the most effective treatment, the majority of patients experience relapse and die of the disease. The major cause of treatment failure is the development of multidrug resistance. The BM microenvironment confers MM chemoresistance. Deducing how the BM creates a microenvironment friendly to MM cells and confers resistance is thus the key to overcoming drug resistance and greatly improving patient survival. Recently we discovered that human MM- derived MIF (macrophage migration inhibitory factor) regulates the homing or affinity of MM cells for BM and, as a result, their sensitivity to chemotherapy. MIF is highly expressed by human MM cells and the expression levels positively correlate with advanced disease and poor survival in patients. Surprisingly, knocking down MIF in MM cells impaired their adhesion to BM stromal cells (BMSCs) in vitro and led to formation of extramedullary tumors in SCID mice. More importantly, MIF-knockdown human MM cells were more sensitive, compared with control cells, to chemotherapy in SCID mice because chemotherapy effectively eradicated extramedullary but not intramedullary tumors in the host. Inhibiting MIF activity in MM cells (cell lines and primary MM cells from patients) by the MIF inhibitor (4-IPP) or neutralizing mAbs also resulted in impaired adhesion to BMSCs in vitro and formation of extramedullary tumors in SCID and SCID-hu mice without affecting tumor burdens. Furthermore, MM-(transwell)-conditioned human BMSCs mediated stronger adhesion to MM cells, provided greater protection to MM cells against chemotherapy-induced apoptosis, and attracted more monocytes than MIF-knockdown MM-conditioned BMSCs. Based on these novel findings, we hypothesize that high MIF in MM cells contributes to poor patient survival by enhancing the affinity of MM cells for BM and by conditioning BM to become a MM-friendly microenvironment, leading to enhanced MM growth and survival and induction of drug resistance. Aim 1 will elucidate the mechanisms of MM-derived MIF in regulating MM homing to and affinity for BM. Aim 2 will determine the importance and mechanisms of MM- derived MIF in conditioning BM to become a MM-friendly microenvironment, and Aim 3 will determine and validate the role of MM-expressing MIF in patients with MM. Accomplishing these aims will provide the justification and tools for developing novel and effective strategies to target MIF to improve the therapeutic efficacy of chemotherapy. The proposed studies will also lead to a better understanding of the fundamental mechanisms underlying MM homing or metastasis to the bone and MM conditioning the microenvironment, and could pave the way to the first substantial improvements in current MM treatment by mobilizing MM cells away from the protective BM microenvironment.

项目概要 多发性骨髓瘤 (MM)，其特征是恶性浆细胞在骨髓 (BM) 中积聚， 是美国最常见的骨恶性肿瘤。虽然化疗是最有效的 治疗后，大多数患者会复发并死于疾病。治疗的主要原因 失败是多重耐药性的发展。 BM 微环境赋予 MM 化学耐药性。 因此，推断BM如何创造对MM细胞友好的微环境并赋予其抵抗力是关键 克服耐药性并大大提高患者的生存率。最近我们发现人类MM- 衍生的 MIF（巨噬细胞迁移抑制因子）调节 MM 细胞对 BM 的归巢或亲和力， 结果，他们对化疗的敏感性增加。 MIF 在人 MM 细胞中高表达，并且表达量 水平与患者的晚期疾病和较差的生存率呈正相关。令人惊讶的是，击倒 MM细胞中的MIF在体外损害了它们与BM基质细胞（BMSC）的粘附，并导致形成 SCID 小鼠的髓外肿瘤。更重要的是，MIF 敲低的人类 MM 细胞更加敏感， 与对照细胞相比，对 SCID 小鼠进行化疗，因为化疗有效地根除 宿主体内的髓外肿瘤但不是髓内肿瘤。抑制 MM 细胞（细胞系和 MIF 抑制剂 (4-IPP) 或中和 mAb 也会导致（来自患者的原代 MM 细胞）受损 体外与 BMSC 的粘附以及 SCID 和 SCID-hu 小鼠髓外肿瘤的形成 影响肿瘤负荷。此外，MM-(transwell) 条件的人 BMSC 介导更强的粘附 为 MM 细胞提供更大的保护，防止化疗诱导的细胞凋亡，并吸引 比 MIF 敲低 MM 条件的 BMSC 具有更多的单核细胞。基于这些新颖的发现，我们 假设 MM 细胞中的高 MIF 通过增强 MM 细胞的亲和力导致患者生存率下降 BM 并通过调节 BM 使其成为 MM 友好的微环境，从而促进 MM 生长 以及耐药性的存活和诱导。目标 1 将阐明 MM 衍生的 MIF 的机制 调节 MM 归巢和对 BM 的亲和力。目标 2 将确定 MM-的重要性和机制 衍生的 MIF 调节 BM 成为 MM 友好的微环境，目标 3 将确定并 验证表达 MM 的 MIF 在 MM 患者中的作用。实现这些目标将提供 开发针对 MIF 的新颖有效策略以改善治疗的理由和工具 化疗的疗效。拟议的研究还将有助于更好地理解基本原理 MM 归巢或转移到骨的机制以及 MM 调节微环境的机制， 并可以通过动员 MM 细胞，为当前 MM 治疗的首次实质性改进铺平道路 远离保护性 BM 微环境。