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.
Highlights
Extracellular vesicle (EV) is an important mode of intercellular communication, besides soluble factor and tunneling nanotubule
Our previous study showed that that BCR/ABL hybrid gene could be transferred from K562 EVs to HEK293 cells or neutrophils [4]
SD rats, injected with K562 EVs, showed some characteristics of chronic myeloid leukemia (CML), e.g., feeble, febrile, thin, with splenomegaly and neutrophilia (Figure 1A), but with reduced neutrophil phagocytic activity (Figure 1B), similar to those seen in CML [16]
Summary
Extracellular vesicle (EV) is an important mode of intercellular communication, besides soluble factor and tunneling nanotubule. Several studies have shown that in addition to proteins, mRNAs, and microRNAs, there are DNA fragments within EVs [4,5,6,7,8]. Our previous study showed the existence of DNA in EVs that could be transferred from one cell to another by endocytosis or fusion. The transferred EV DNAs have pathophysiological significance, to increase the DNA-coding mRNA and protein levels, and influence the function of the recipient cells [4]. There is increasing evidence that EVs play a pivotal role in tumorigenesis, which can occur in adjacent and remote locations. EVs shed from tumor cells have the potential to increase tumor survival and expansion, independent of cell-to-cell contact
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