Abstract
Although major advances have been achieved in the treatment of chronic myeloid leukemia (CML) by using tyrosine kinase inhibitors, patients relapse after withdrawal and need long-term medication. This reflects the CML clones have not been eliminated completely. The precise mechanisms for the maintenance of CML cells are not yet fully understood. The bone marrow microenvironment constitutes the sanctuary for leukemic cells. Mesenchymal stem cells (MSC) are an important component of the bone marrow microenvironment (BM). It plays an important role in the development and drug resistance of CML. Accumulating evidence indicates that exosomes play a vital role in cell-to-cell communication. We successfully isolated and purified exosomes from human bone marrow microenvironment-derived mesenchymal stem cells (hBMMSC-Exo) by serial centrifugation. In the present study, we investigated the effect of hBMMSC-Exo on the proliferation, apoptosis, and drug resistance of CML cells. The results demonstrated that hBMMSC-Exo had the ability to inhibit the proliferation of CML cells in vitro via miR-15a and arrest cell cycle in the G0/G1 phase. However, the results obtained from BALB/c nu/nu mice studies apparently contradicted the in vitro results. In fact, hBMMSC-Exo increased tumor incidence and promoted tumor growth in vivo. Further study showed the antiapoptotic protein Bcl-2 expression increased, whereas the Caspase3 expression decreased. Moreover, the in vivo study in the xenograft tumor model showed that hBMMSC-Exo promoted the proliferation and decreased the sensitivity of CML cells to tyrosine kinase inhibitors, resulting in drug resistance. These results demonstrated that hBMMSC-Exo supported the maintenance of CML cells and drug resistance in BM by cell-extrinsic protective mechanisms. They also suggested that hBMMSC-Exo might be a potential target to overcome the microenvironment-mediated drug resistance.
Highlights
Chronic myeloid leukemia (CML) is a disorder caused by the BCR/ABL fusion gene
We investigated the effect of hBMMSC-Exo on the proliferation, apoptosis, and drug resistance of CML cells
We found that the levels of miR15a expression in K562 cells increased with the concentrations of cocultured hBMMSC-Exo, suggesting the transfer of miR-15a from hBMMSC-Exo to CML cells
Summary
Chronic myeloid leukemia (CML) is a disorder caused by the BCR/ABL fusion gene. Tyrosine kinase inhibitors (TKI), as one of the most successful molecular targeted drugs in modern medical history, transformed the natural history and prognosis of CML [1]. Some studies have suggested it may be related to the BCR-ABL overexpression, the point mutations in the kinase domain of BCR/ABL, TP53 deletion [6,7,8], etc. Besides these intrinsic factors, some extrinsic factors are very important. Stem Cells International are an important component of the bone marrow microenvironment. We investigated the effect of hBMMSC-Exo on the proliferation, apoptosis, and drug resistance of CML cells
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