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  • Acute myeloid leukemia encourages bone marrow mesenchymal stromal cells to express PI3K/AKT pathway genes through exosome secretion
  • Maryam Nabigol,1 Mehdi Allahbakhshian Farsani,2,*
    1. Department of Hematology and blood bank, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
    2. Department of Hematology and blood bank, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran


  • Introduction: Introduction: Acute Myeloid Leukemia (AML) is a heterogeneous clonal disorder characterized by the uncontrolled expansion and differentiation arrest of myeloid cells. While a wide range of therapeutic approaches have been developed for this neoplasm, therapy resistance and relapse are still the main obstacles. Currently, it is well known that the components of the bone marrow microenvironment, including mesenchymal stromal cells (MSCs), play a crucial role in leukemia growth and inducing anti-apoptotic signals, resulting in treatment failures of AML. PI3K/AKT signaling is one of the pathways involved in leukemic cell growth, whose hyperactivation in MSCs is associated with leukemogenesis. It is important to note that the interaction between MSCs and AML cells occurs either through direct cell-to-cell contact or indirectly through soluble mediators, including cytokines or extracellular vesicles (EVs). Exosomes are membrane-bound EVs that transfer various cargoes of chemicals and have an important role in pathophysiological conditions. In AML, leukemia-derived exosomes transform MSCs to create a microenvironment that promotes chemoresistance and leukemia survival. In this study, we examined the influence of AML-derived exosomes on the alteration in the expression of genes (PI3K, AKT, and mTOR) involved in PI3K/AKT signaling as a favoring leukemia pathway.
  • Methods: Methods: Exosomes were isolated from the HL-60 cell line. The morphology, size, and CD markers of isolated particles were assessed using TEM (Transmission Electron Microscopy), DLS (Dynamic Light Scattering) technique, and flow cytometry, respectively. Exosomal protein content was assessed using a BCA protein assay in order to determine the concentration of exosomes. MSCs were co-cultured with 20, 50, and 80 μg/mL concentrations of AML-exosomes. The effect of AML-exosomes on the MSCs' metabolic activity was evaluated by an MTT assay. Gene expression analysis was performed by qRT-PCR.
  • Results: Results: Isolated exosomes were mostly positive for exosomal CD markers, including CD9, CD63, and CD81. According to the DLS results, the isolated particles' size range was between 70-110 nm. Our results demonstrated that treatment with 50 μg/mL of AML-exosomes increased MSCs' metabolic activity, while exposure to 80 μg/mL of exosomes decreased the metabolic activity of these cells (P<0.05). Additionally, qRT-PCR results showed that PI3K, AKT, and mTOR were significantly upregulated in response to the treatment with exosomes in MSCs.
  • Conclusion: Conclusion: Since PI3K/AKT signaling is involved in leukemogenesis, our findings suggest that AML-exosomes induce MSCs to express PI3K/AKT genes and activate this pathway, which may contribute to the initiation and development of AML in the bone marrow microenvironment.
  • Keywords: Keywords: Acute myeloid leukemia, Exosome, Mesenchymal stromal cell, PI3K/AKT signaling pathway