Chronic myelogenous leukemia cells remodel the bone marrow niche via exosome-mediated transfer of miR-320

Abstract

Rationale: Reciprocal interactions between leukemic cells and bone marrow mesenchymal stromal cells (BMMSC) remodel the normal niche into a malignant niche, leading to leukemia progression. Exosomes have emerged as an essential mediator of cell-cell communication. Whether leukemic exosomes involved in bone marrow niche remodeling remains unknown.Methods: We investigated the role of leukemic exosomes in molecular and functional changes of BMMSC in vitro and in vivo. RNA sequencing and bioinformatics were employed to screen for miRNAs that are selectively sorted into leukemic exosomes and the corresponding RNA binding proteins.Results: We demonstrated that leukemia cells significantly inhibited osteogenesis by BMMSC both in vivo and in vitro. Some tumor suppressive miRNAs, especially miR-320, were enriched in exosomes and thus secreted by leukemic cells, resulting in increased proliferation of the donor cells. In turn, the secreted exosomes were significantly endocytosed by adjacent BMMSC and thus inhibited osteogenesis at least partially via β-catenin inhibition. Mechanistically, miR-320 and some other miRNAs were sorted out into the exosomes by RNA binding protein heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1), as these miRNAs harbor the recognition site for HNRNPA1.Conclusion: HNRNPA1-mediated exosomal transfer of miR-320 from leukemia cells to BMMSC is an important mediator of leukemia progression and is a potential therapeutic target for CML.

CD63+ Cancer‐Associated Fibroblasts Confer Tamoxifen Resistance to Breast Cancer Cells through Exosomal miR‐22

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The role of miR-320 in glucose and lipid metabolism disorder-associated diseases

“…Exosomes are naturally released from living cells and have been well recognized to play critical roles in mediating cell-to-cell communication [132]. It is worth mentioning that the current studies about the exosomal transfer of miR-320 mainly focus on cancers [133][134][135]. For example, Stevic et al determined the miRNA profiles in exosomes from plasma of 106 epithelial ovarian cancer patients, 8 ovarian cystadenoma patients, and 29 healthy women, and they found that miR-320 was significantly enriched in the exosomes from plasma of epithelial ovarian cancer patients as compared to those of healthy women [133].…”

Mononuclear phagocyte system blockade improves therapeutic exosome delivery to the myocardium

“…Exosomes, which are small membrane vesicles of 30-200 nm in diameter, are secreted by different types of cells and are emerging as a novel mediator of intercellular communication and drug delivery vehicles 1, 2. As naturally derived nanovesicles, exosomes efficiently deliver exogenous RNAs (siRNAs and miRNAs) to target tissues/cells in vivo 3.…”