title: Transferred BCR/ABL DNA from K562 extracellular vesicles causes chronic myeloid leukemia in immunodeficient mice.
abstract: Our previous study showed that besides mRNAs and microRNAs, there are DNA fragments within extracellular vesicles (EVs). The BCR/ABL hybrid gene, involved in the pathogenesis of chronic myeloid leukemia (CML), could be transferred from K562 EVs to neutrophils and decrease their phagocytic activity in vitro. Our present study provides evidence that BCR/ABL DNAs transferred from EVs have pathophysiological significance in vivo. Two months after injection of K562 EVs into the tail vein of Sprague-Dawley (SD) rats, they showed some characteristics of CML, e.g., feeble, febrile, and thin, with splenomegaly and neutrophilia but with reduced neutrophil phagocytic activity. These findings were also observed in immunodeficient NOD/SCID mice treated with K562 EVs; BCR/ABL mRNA and protein were found in their neutrophils. The administration of actinomycin D, an inhibitor of de novo mRNA synthesis, prevented the abnormalities caused by K562 EVs in NOD/SCID mice related to CML, including neutrophilia and bone marrow hyperplasia. As a specific inhibitor of tyrosine kinases, imatinib blocked the activity of tyrosine kinases and the expression of phospho-Crkl, induced by the de novo BCR/ABL protein caused by K562 EVs bearing BCR/ABL DNA. Our current study shows the pathophysiological significance of transferred tumor gene from EVs in vivo, which may represent an important mechanism for tumorigenesis, tumor progression, and metastasis.
authors.affiliation: Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China; Clinic of Health Service, Logistics Department, Air Force of Nanjing Area Command, Nanjing, Jiangsu, P.R. China.
authors.forename: Jin
authors.initials: J
authors.lastname: Cai
authors.affiliation: Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China.
authors.forename: Gengze
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Tan
authors.affiliation: Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China.
authors.forename: Caiyu
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China.
authors.forename: Chuanwei
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China.
authors.forename: Na
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China.
authors.forename: Xue
authors.initials: X
authors.lastname: Zou
authors.affiliation: Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China.
authors.forename: Xinjian
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China.
authors.forename: Faying
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China.
authors.forename: Duofen
authors.initials: D
authors.lastname: He
authors.affiliation: Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Division of Nephrology, Departments of Medicine and Physiology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Jose
authors.affiliation: Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China.
authors.forename: Chunyu
authors.initials: C
authors.lastname: Zeng
mesh_terms: D000818:Animals; D002460:Cell Line; D004247:DNA / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology*; D051379:Mice; D016513:Mice, SCID; D009504:Neutrophils / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D004247:DNA; D016044:Fusion Proteins, bcr-abl