title: Potential role of exosome-associated microRNA panels and in vivo environment to predict drug resistance for patients with multiple myeloma.
abstract: Multiple myeloma (MM) is the second most common hematologic neoplasms and an appropriate in vivo environment for myeloma cells has potential implications for initiation, progression, and metastasis of MM. Exosomes, entities carrying microRNAs (miRNAs) to target locations, participate in the cross-talk between myeloma cells and nonmalignant components of the in vivo environment. This study disclosed the emerging roles of circulating exosome-associated miRNAs in drug resistance (DR) of MM. To this end, the medical records of consecutively hospitalized MM patients, who received novel agents-based therapies, were analyzed. Then, an optimized procedure was established for exosome isolation and exosomal RNA analysis. The exosome-associated miRNA expression patterns for predicting bortezomib (Bz) resistance of MM were further examined using a microarray. In total, 204 patients were enrolled with DR rates of 36.5%, 73.1% and 81.8% in the bortezomib (Bz), thalidomide and lenalidomide containing groups. The serum total light chain ratio ≥ 100, CRP ≥ 20 mg/L, and the second-line usage increased risks of acquired Bz-resistance. Among 68 cases having genetic tests, a high risk factor for predicting de novo DR was 1q21 amplification, which also correlated with lower levels of cholesterol and LDL-C. Moreover, nano-sized exosomes were isolated with significantly increasing internal RNAs and down-regulation of exosomal miR-16-5p, miR-15a-5p and miR-20a-5p, miR-17-5p was revealed in the patients resistant to Bz. The routine workup of MM hardly suggested a value for DR prediction. The circulating exosomes carrying miRNAs provided a window that permits a better understanding of the in vivo intercellular crosstalk in MM patients.
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, Chengdu, China.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Pan
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Xiang
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Huanling
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Radiology, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Pujun
authors.initials: P
authors.lastname: Guan
authors.affiliation: Department of Hematology, Affiliated Hospital of North Sichuan Medical College, Nanchang, China.
authors.forename: Xingli
authors.initials: X
authors.lastname: Zou
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: C Alexander
authors.initials: CA
authors.lastname: Valencia
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Biao
authors.initials: B
authors.lastname: Dong
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Xie
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Ma
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Dong
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Shuai
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Niu
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood / Q000378:metabolism; D000069286:Bortezomib / Q000494:pharmacology / Q000627:therapeutic use; D002097:C-Reactive Protein / Q000032:analysis; D002869:Chromosome Aberrations; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D018450:Disease Progression; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D055354:Exosomes / Q000378:metabolism*; D005260:Female; D005784:Gene Amplification; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000097:blood; D000077269:Lenalidomide; D008297:Male; D035683:MicroRNAs / Q000097:blood* / Q000378:metabolism; D046228:Microarray Analysis; D008875:Middle Aged; D009101:Multiple Myeloma / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D011237:Predictive Value of Tests; D012307:Risk Factors; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007147:Immunoglobulin Light Chains; D035683:MicroRNAs; D013792:Thalidomide; D000069286:Bortezomib; D002097:C-Reactive Protein; D000077269:Lenalidomide
keywords: exosome; microRNA; microvesicle; myeloma; resistance