Role of MIF in myeloma bone homing and drug response

项目摘要 多发性骨髓瘤（MM），特征在于恶性浆细胞在骨髓（BM）中的积聚， 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 失败是多药耐药性的发展。BM微环境赋予MM化学抗性。 因此，推断BM如何创造对MM细胞友好的微环境并赋予抗性是关键 克服耐药性，大大提高病人的生存率。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， 因此，他们对化疗的敏感性。MIF在人MM细胞中高度表达， 水平与患者的晚期疾病和较差的存活率正相关。令人惊讶的是， 在体外，MM细胞中的MIF损害了它们与BM基质细胞（BMSC）的粘附，并导致 SCID小鼠的髓外肿瘤。更重要的是，MIF-knockdown人MM细胞更敏感， 与对照细胞相比，由于化疗有效地根除了SCID小鼠中的化疗 宿主的髓外肿瘤而不是髓内肿瘤。抑制MM细胞（细胞系和细胞系）中的MIF活性 通过MIF抑制剂（4-IPP）或中和mAb， 在SCID和SCID-hu小鼠中， 影响肿瘤负荷。此外，MM-（transwell）条件化的人BMSCs介导更强的粘附， MM细胞，为MM细胞提供了更大的保护，以对抗化疗诱导的凋亡，并吸引 单核细胞比MIF敲除MM条件BMSC更多。基于这些新发现，我们 假设MM细胞中较高的MIF通过增强MM细胞的亲和力而导致患者存活率差 并通过调节BM成为MM友好的微环境，导致增强的MM生长 以及存活和诱导耐药性。目的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- 在调节BM成为MM友好的微环境中导出MIF，目标3将确定并 验证MM表达MIF在MM患者中的作用。实现这些目标将为MM患者提供 开发新的和有效的靶向MIF的策略，以改善治疗的合理性和工具， 化疗的疗效。拟议的研究也将导致更好地了解基本的 MM归巢或转移到骨的潜在机制以及MM调节微环境， 并且可以通过动员MM细胞为当前MM治疗的首次实质性改进铺平道路 远离保护性的骨髓微环境

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.