Extracellular vesicle cargo dynamics in the bone marrow microenvironment: from hematopoietic homeostasis to malignant transformation

The bone marrow (BM) microenvironment relies on extracellular vesicle (EV)-mediated communication to maintain hematopoietic homeostasis and contribute to cellular responses in malignant transformation. EV function as molecular shuttles carrying miRNAs, proteins, and lipids that regulate hematopoietic stem cell (HSC) self-renewal, quiescence, and lineage commitment. HSC-derived EVs can stimulate stem cell factor (SCF) expression in recipient HSCs through autocrine/paracrine signaling, while mesenchymal stem cell (MSC)-EVs modulate HSC differentiation via TLR4 activation and miRNA transfer. Regulated EV biogenesis pathways, involving tetraspanins, ESCRT components, and lipid-sorting mechanisms, control cargo selection and secretion in both HSCs and BM cells. During malignant transformation, EV cargo composition shifts dramatically: leukemic cells release EVs enriched in immunosuppressive factors, pro-survival signals, and drug resistance mediators that reprogram the BM microenvironment to support tumor growth. These changes—driven by hypoxia, inflammatory signaling, metabolic reprogramming, and chemotherapeutic pressure—enable tumor-derived EVs to induce HSC quiescence, polarize macrophages toward immunosuppressive phenotypes, and promote stromal cell transformation. The distinct protein and miRNA profiles of EVs from malignant versus healthy cells offer diagnostic and prognostic value, positioning EVs as both biomarkers and therapeutic targets. This review examines EV cargo composition and functional roles in normal and malignant hematopoiesis, emphasizing dynamic changes that accompany disease progression and their clinical implications.