Modulation of the bone marrow microenvironment by acute B-cell lymphoblastic leukemia-derived large oncosomes

Within the bone marrow microenvironment, leukemia cells can hijack regulatory intercellular communication routes usually employed by benign hematopoietic cells and establish a microenvironment permissive for (chemo-)therapy-evasive growth. An important means of transmitting signals by leukemia cells is the release of extracellular vesicles (EVs). Large oncosomes (LO) are a distinct population of EVs known to contribute to aggressive growth in solid tumors. Here, we show that BCR-ABL1+ B-cell acute lymphoblastic leukemia (B-ALL) cells release LO capable of reprogramming primary mesenchymal stromal cells (MSC) towards a tumor growth-supportive phenotype. Transcriptome analysis combined with targeted secretome profiling of MSC revealed that BCR-ABL1+ B-ALL cells use LO to modulate pathways previously shown to regulate the availability of insulin-like growth factor (IGF) 1 in the bone marrow microenvironment. Specifically, LO-conditioned MSC secrete less inhibitory IGF binding proteins (IGFBPs) and show altered expression of extracellular matrix-degrading fibrinolytic proteins. Furthermore, LO metabolically reprogram MSC and prime MSC towards differentiation into adipocytes capable of sustaining B-ALL cell growth. Thus, LO-educated MSC, and the adipocytes derived from them, support B-ALL cells by distinct mechanisms, and targeting of LO-mediated communication pathways to prevent B-ALL progression has potential for the development of novel adjuvant treatment strategies.