title: Role of Myeloma-Derived MIF in Myeloma Cell Adhesion to Bone Marrow and Chemotherapy Response.
abstract: Multiple myeloma (MM) remains an incurable cancer characterized by accumulation of malignant plasma cells in the bone marrow (BM). The mechanism underlying MM homing to BM is poorly elucidated.
  
  
  
  The clinical significance of migration inhibitory factor (MIF) expression was examined by analyzing six independent gene expression profile databases of primary MM cells using the Student's t test and Kaplan-Meier test. Enzyme-linked immunosorbent assay was used to examine MIF expression. In vivo bioluminescent imaging was used to determine MM cell localization and treatment efficacy in human MM xenograft mouse models, with three to four mice per group. MM cell attachment to BM stromal cells (BMSCs) was monitored by cell adhesion assay. MIF regulation of the expression of adhesion molecules was determined by chromatin immunoprecipitation (ChIP) assay. Statistical tests were two-sided.
  
  
  
  High levels of MIF were detected in MM BM (MIF level in BM plasma: healthy = 10.72 ± 5.788 ng/mL, n = 5; MM = 1811 ± 248.7 ng/mL, n = 10; P < .001) and associated with poor survival of patients (Kaplan-Meier test for MM OS: 87 MIF(high) patients, 86 MIF(low) patients, P = .02). Knocking down MIF impaired MM cell adhesion to BMSCs in vitro and led to formation of extramedullary tumors in SCID mice. MIF acted through surface receptor CXCR4 and adaptor COPS5 to regulate the expression of adhesion molecules ALCAM, ITGAV, and ITGB5 on MM cells. More importantly, MIF-deficient MM cells were sensitive to chemotherapy in vitro when cocultured with BMSCs and in vivo. MIF inhibitor 4-IPP sensitized MM cells to chemotherapy.
  
  
  
  MIF is an important player and a novel therapeutic target in MM. Inhibiting MIF activity will sensitize MM cells to chemotherapy.
authors.affiliation: Affiliations of authors: Department of Hematology and State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, West China Hospital, China (YZ); Department of Cancer Biology (YZ, QW, TL, JQ, YLu, YLi, EB, QY), Taussig Cancer Center (FR), Imaging Core Facility, Lerner Research Institute (JD), and Department of Pathology and Laboratory Medicine Institute (EH), Cleveland Clinic, Cleveland, OH; Department of Hematology, Zhejiang University, China (YLi, ZC); Department of Internal Medicine, Weiss Memory Hospital, Chicago, IL (YQ); Department of Lymphoma/Myeloma, MD Anderson Cancer Center, Houston, TX (JY).
authors.forename: Yuhuan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Affiliations of authors: Department of Hematology and State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, West China Hospital, China (YZ); Department of Cancer Biology (YZ, QW, TL, JQ, YLu, YLi, EB, QY), Taussig Cancer Center (FR), Imaging Core Facility, Lerner Research Institute (JD), and Department of Pathology and Laboratory Medicine Institute (EH), Cleveland Clinic, Cleveland, OH; Department of Hematology, Zhejiang University, China (YLi, ZC); Department of Internal Medicine, Weiss Memory Hospital, Chicago, IL (YQ); Department of Lymphoma/Myeloma, MD Anderson Cancer Center, Houston, TX (JY).
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Affiliations of authors: Department of Hematology and State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, West China Hospital, China (YZ); Department of Cancer Biology (YZ, QW, TL, JQ, YLu, YLi, EB, QY), Taussig Cancer Center (FR), Imaging Core Facility, Lerner Research Institute (JD), and Department of Pathology and Laboratory Medicine Institute (EH), Cleveland Clinic, Cleveland, OH; Department of Hematology, Zhejiang University, China (YLi, ZC); Department of Internal Medicine, Weiss Memory Hospital, Chicago, IL (YQ); Department of Lymphoma/Myeloma, MD Anderson Cancer Center, Houston, TX (JY).
authors.forename: Tianshu
authors.initials: T
authors.lastname: Li
authors.affiliation: Affiliations of authors: Department of Hematology and State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, West China Hospital, China (YZ); Department of Cancer Biology (YZ, QW, TL, JQ, YLu, YLi, EB, QY), Taussig Cancer Center (FR), Imaging Core Facility, Lerner Research Institute (JD), and Department of Pathology and Laboratory Medicine Institute (EH), Cleveland Clinic, Cleveland, OH; Department of Hematology, Zhejiang University, China (YLi, ZC); Department of Internal Medicine, Weiss Memory Hospital, Chicago, IL (YQ); Department of Lymphoma/Myeloma, MD Anderson Cancer Center, Houston, TX (JY).
authors.forename: Jianfei
authors.initials: J
authors.lastname: Qian
authors.affiliation: Affiliations of authors: Department of Hematology and State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, West China Hospital, China (YZ); Department of Cancer Biology (YZ, QW, TL, JQ, YLu, YLi, EB, QY), Taussig Cancer Center (FR), Imaging Core Facility, Lerner Research Institute (JD), and Department of Pathology and Laboratory Medicine Institute (EH), Cleveland Clinic, Cleveland, OH; Department of Hematology, Zhejiang University, China (YLi, ZC); Department of Internal Medicine, Weiss Memory Hospital, Chicago, IL (YQ); Department of Lymphoma/Myeloma, MD Anderson Cancer Center, Houston, TX (JY).
authors.forename: Yong
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Affiliations of authors: Department of Hematology and State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, West China Hospital, China (YZ); Department of Cancer Biology (YZ, QW, TL, JQ, YLu, YLi, EB, QY), Taussig Cancer Center (FR), Imaging Core Facility, Lerner Research Institute (JD), and Department of Pathology and Laboratory Medicine Institute (EH), Cleveland Clinic, Cleveland, OH; Department of Hematology, Zhejiang University, China (YLi, ZC); Department of Internal Medicine, Weiss Memory Hospital, Chicago, IL (YQ); Department of Lymphoma/Myeloma, MD Anderson Cancer Center, Houston, TX (JY).
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Affiliations of authors: Department of Hematology and State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, West China Hospital, China (YZ); Department of Cancer Biology (YZ, QW, TL, JQ, YLu, YLi, EB, QY), Taussig Cancer Center (FR), Imaging Core Facility, Lerner Research Institute (JD), and Department of Pathology and Laboratory Medicine Institute (EH), Cleveland Clinic, Cleveland, OH; Department of Hematology, Zhejiang University, China (YLi, ZC); Department of Internal Medicine, Weiss Memory Hospital, Chicago, IL (YQ); Department of Lymphoma/Myeloma, MD Anderson Cancer Center, Houston, TX (JY).
authors.forename: Enguang
authors.initials: E
authors.lastname: Bi
authors.affiliation: Affiliations of authors: Department of Hematology and State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, West China Hospital, China (YZ); Department of Cancer Biology (YZ, QW, TL, JQ, YLu, YLi, EB, QY), Taussig Cancer Center (FR), Imaging Core Facility, Lerner Research Institute (JD), and Department of Pathology and Laboratory Medicine Institute (EH), Cleveland Clinic, Cleveland, OH; Department of Hematology, Zhejiang University, China (YLi, ZC); Department of Internal Medicine, Weiss Memory Hospital, Chicago, IL (YQ); Department of Lymphoma/Myeloma, MD Anderson Cancer Center, Houston, TX (JY).
authors.forename: Frederic
authors.initials: F
authors.lastname: Reu
authors.affiliation: Affiliations of authors: Department of Hematology and State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, West China Hospital, China (YZ); Department of Cancer Biology (YZ, QW, TL, JQ, YLu, YLi, EB, QY), Taussig Cancer Center (FR), Imaging Core Facility, Lerner Research Institute (JD), and Department of Pathology and Laboratory Medicine Institute (EH), Cleveland Clinic, Cleveland, OH; Department of Hematology, Zhejiang University, China (YLi, ZC); Department of Internal Medicine, Weiss Memory Hospital, Chicago, IL (YQ); Department of Lymphoma/Myeloma, MD Anderson Cancer Center, Houston, TX (JY).
authors.forename: Yu
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Affiliations of authors: Department of Hematology and State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, West China Hospital, China (YZ); Department of Cancer Biology (YZ, QW, TL, JQ, YLu, YLi, EB, QY), Taussig Cancer Center (FR), Imaging Core Facility, Lerner Research Institute (JD), and Department of Pathology and Laboratory Medicine Institute (EH), Cleveland Clinic, Cleveland, OH; Department of Hematology, Zhejiang University, China (YLi, ZC); Department of Internal Medicine, Weiss Memory Hospital, Chicago, IL (YQ); Department of Lymphoma/Myeloma, MD Anderson Cancer Center, Houston, TX (JY).
authors.forename: Judy
authors.initials: J
authors.lastname: Drazba
authors.affiliation: Affiliations of authors: Department of Hematology and State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, West China Hospital, China (YZ); Department of Cancer Biology (YZ, QW, TL, JQ, YLu, YLi, EB, QY), Taussig Cancer Center (FR), Imaging Core Facility, Lerner Research Institute (JD), and Department of Pathology and Laboratory Medicine Institute (EH), Cleveland Clinic, Cleveland, OH; Department of Hematology, Zhejiang University, China (YLi, ZC); Department of Internal Medicine, Weiss Memory Hospital, Chicago, IL (YQ); Department of Lymphoma/Myeloma, MD Anderson Cancer Center, Houston, TX (JY).
authors.forename: Eric
authors.initials: E
authors.lastname: Hsi
authors.affiliation: Affiliations of authors: Department of Hematology and State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, West China Hospital, China (YZ); Department of Cancer Biology (YZ, QW, TL, JQ, YLu, YLi, EB, QY), Taussig Cancer Center (FR), Imaging Core Facility, Lerner Research Institute (JD), and Department of Pathology and Laboratory Medicine Institute (EH), Cleveland Clinic, Cleveland, OH; Department of Hematology, Zhejiang University, China (YLi, ZC); Department of Internal Medicine, Weiss Memory Hospital, Chicago, IL (YQ); Department of Lymphoma/Myeloma, MD Anderson Cancer Center, Houston, TX (JY).
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Affiliations of authors: Department of Hematology and State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, West China Hospital, China (YZ); Department of Cancer Biology (YZ, QW, TL, JQ, YLu, YLi, EB, QY), Taussig Cancer Center (FR), Imaging Core Facility, Lerner Research Institute (JD), and Department of Pathology and Laboratory Medicine Institute (EH), Cleveland Clinic, Cleveland, OH; Department of Hematology, Zhejiang University, China (YLi, ZC); Department of Internal Medicine, Weiss Memory Hospital, Chicago, IL (YQ); Department of Lymphoma/Myeloma, MD Anderson Cancer Center, Houston, TX (JY).
authors.forename: Zhen
authors.initials: Z
authors.lastname: Cai
authors.affiliation: Affiliations of authors: Department of Hematology and State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, West China Hospital, China (YZ); Department of Cancer Biology (YZ, QW, TL, JQ, YLu, YLi, EB, QY), Taussig Cancer Center (FR), Imaging Core Facility, Lerner Research Institute (JD), and Department of Pathology and Laboratory Medicine Institute (EH), Cleveland Clinic, Cleveland, OH; Department of Hematology, Zhejiang University, China (YLi, ZC); Department of Internal Medicine, Weiss Memory Hospital, Chicago, IL (YQ); Department of Lymphoma/Myeloma, MD Anderson Cancer Center, Houston, TX (JY).
authors.forename: Qing
authors.initials: Q
authors.lastname: Yi
mesh_terms: D020410:Activated-Leukocyte Cell Adhesion Molecule / Q000235:genetics; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000378:metabolism; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D019898:Autocrine Communication; D001853:Bone Marrow / Q000378:metabolism; D000069286:Bortezomib / Q000494:pharmacology; D000075686:COP9 Signalosome Complex; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002633:Chemotaxis / Q000235:genetics; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D064593:Heterografts; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D008558:Melphalan / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009368:Neoplasm Transplantation; D010447:Peptide Hydrolases / Q000378:metabolism; D010950:Plasma Cells / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism
chemical_list: C532251:4-iodo-6-phenylpyrimidine; D020410:Activated-Leukocyte Cell Adhesion Molecule; D000944:Antigens, Differentiation, B-Lymphocyte; D018906:Antineoplastic Agents, Alkylating; D000949:Histocompatibility Antigens Class II; D047908:Intracellular Signaling Peptides and Proteins; D008263:Macrophage Migration-Inhibitory Factors; D011743:Pyrimidines; D012333:RNA, Messenger; D019718:Receptors, CXCR4; C045084:invariant chain; D000069286:Bortezomib; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human; D008558:Melphalan