Potential role of exosome-associated microRNA panels and in vivo environment to predict drug resistance for patients with multiple myeloma
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Li Zhang1,2,*, Ling Pan1,*, Bing Xiang1, Huanling Zhu1, Yu Wu1, Meng Chen1, Pujun Guan3, Xingli Zou4, C Alexander Valencia5, Biao Dong6, Jianjun Li1, Liping Xie1, Hongbing Ma1, Fangfang Wang1, Tian Dong1, Xiao Shuai1, Ting Niu1, Ting Liu1
1Department of Hematology, West China Hospital, Sichuan University, Chengdu, China
2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
3Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
4Department of Hematology, Affiliated Hospital of North Sichuan Medical College, Nanchang, China
5Division of Human Genetics, Cincinnati Children’s Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
6State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
*These authors contributed equally to this work
Ting Niu, email: [email protected]
Ting Liu, email: [email protected]
Keywords: myeloma, resistance, exosome, microvesicle, microRNA
Received: October 15, 2015 Accepted: March 31, 2016 Published: April 26, 2016
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.
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