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.

项目摘要 多发性骨髓瘤（MM），其特征是骨髓（BM）中的恶性血浆细胞积累 是美国最常见的骨恶性肿瘤。虽然化学疗法是最有效的 治疗，大多数患者患有复发和死亡。主要治疗原因 故障是多药电阻的发展。 BM微环境赋予MM化学抗性。 因此，推论BM如何创建对MM细胞友好的微环境并赋予阻力是关键 克服耐药性并大大改善患者的生存。最近，我们发现人类的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，并且 结果，它们对化学疗法的敏感性。 MIF由人类MM细胞高度表达和表达 水平与患者的晚期疾病呈正相关。令人惊讶的是，撞倒了 MM细胞中的MIF在体外损害了其对BM基质细胞（BMSC）的粘附，并导致形成 SCID小鼠中的外肿瘤。更重要的是，MIF knockdown人MM细胞更敏感， 与对照细胞相比，与SCID小鼠的化学疗法相比，因为化学疗法有效地消除了 宿主中的外肺外肿瘤，但不是髓内肿瘤。抑制MM细胞中MIF活性（细胞系和 MIF抑制剂（4-ipp）或中和mAb的原代MM细胞也导致受损 在体外对BMSC的粘附以及SCID和SCID-HU小鼠中的胸外肿瘤的形成 影响肿瘤负担。此外，mm-（transwell）调节的人BMSC介导了更强的粘附力 到MM细胞，为MM细胞提供了更大的保护，以防止化学疗法诱导的细胞凋亡，并吸引 比MIF-KNOCKDOWN MM条件BMSC的单核细胞更多。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细胞的亲和力而导致患者生存不良 BM并通过调节BM成为MM友好的微环境，从而增强了MM的增长 以及耐药性的生存和诱导。 AIM 1将阐明MM衍生MIF的机制 调节MM归巢和对BM的亲和力。 AIM 2将确定MM-的重要性和机制 派生的MIF调节BM成为MM友好的微环境，AIM 3将确定和 验证表达MM的MIF在MM患者中的作用。完成这些目标将为 理由和工具，用于制定针对MIF的新颖有效策略以改善治疗性 化学疗法的功效。拟议的研究还将更好地理解基本 MM归巢或转移到骨骼和MM的机制，调节微环境， 并且可以通过动员MM细胞为当前MM处理的首次实质性改进铺平道路 远离保护性BM微环境。