权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
10078263
负责人：
Qing Yi
金额：
$ 36.94万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10078263
关键词：
Adhesions Affect Affinity Apoptosis Bone Marrow Bone Pain Cancer Etiology Cell Line Cells Chemoresistance Databases Development Disease Disease Management Drug resistance Extramedullary Future Gene Expression Profiling Growth Homing Human Hypercalcemia Impairment In Vitro Injections 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 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 recruit response tool tumor

项目摘要

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.

项目总结

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Enhanced CAR-T activity against established tumors by polarizing human T cells to secrete interleukin-9.

DOI：
10.1038/s41467-020-19672-2
发表时间：
2020-11-19
期刊：
Nature communications
影响因子：
16.6
作者：
Liu L;Bi E;Ma X;Xiong W;Qian J;Ye L;Su P;Wang Q;Xiao L;Yang M;Lu Y;Yi Q
通讯作者：
Yi Q

Therapeutic effects of CSF1R-blocking antibodies in multiple myeloma.

CSF1R 阻断抗体对多发性骨髓瘤的治疗作用

DOI：
10.1038/leu.2017.193
发表时间：
2018-01
期刊：
Leukemia
影响因子：
11.4
作者：
Wang Q;Lu Y;Li R;Jiang Y;Zheng Y;Qian J;Bi E;Zheng C;Hou J;Wang S;Yi Q
通讯作者：
Yi Q

MIF as a biomarker and therapeutic target for overcoming resistance to proteasome inhibitors in human myeloma.

DOI：
10.1182/blood.2020005795
发表时间：
2020-06
期刊：
Blood
影响因子：
20.3
作者：
Qiang Wang;Dongyu Zhao;M. Xian;Zhuo Wang;Enguang Bi;Pan Su;J. Qian;Xingzhe Ma;Maojie Yang;Lintao Liu;Y. Zu;S. Pingali;Kaifu Chen;Z. Cai;Q. Yi
通讯作者：
Qiang Wang;Dongyu Zhao;M. Xian;Zhuo Wang;Enguang Bi;Pan Su;J. Qian;Xingzhe Ma;Maojie Yang;Lintao Liu;Y. Zu;S. Pingali;Kaifu Chen;Z. Cai;Q. Yi

IL-9/STAT3/fatty acid oxidation-mediated lipid peroxidation contributes to Tc9 cell longevity and enhanced antitumor activity.