Abstract
BackgroundAcute myeloid leukemia (AML) is a malignant clonal disease of hematopoietic stem- and progenitor-cell origin. AML features massive proliferation of abnormal blasts and leukemia cells in the bone marrow and the inhibition of normal hematopoiesis at onset. Exosomes containing proteins or nucleic acids are secreted by cells; they participate in intercellular communication and serve as key modulators of hematopoiesis. The purpose of this study was to investigate the effects of exosomes derived from bone marrow mesenchymal stem cells (BMSCs) on the regulation of AML and the underlying mechanisms mediated by microRNA (miRNA).MethodsDysregulated miR-7-5p in AML patients was identified using qRT-PCR and its clinical significance was explored. Bioinformatic analysis revealed the target gene OSBPL11 that could be regulated by miR-7-5p. The findings were validated using a dual-luciferase reporter assay and western blotting. The functional genes of the PI3K/AKT/mTOR signaling pathway were identified, and the functional significance of miR-7-5p in AML cells was determined using a functional recovery assay. AML cells were co-cultured with exosomes originating from BMSCs overexpressing miR-7-5p to determine cell–cell regulation by Exo-miR-7-5p, as well as in vitro and in vivo functional validation via gain- and loss-of-function methods.ResultsExpression of miR-7-5p was decreased in AML patients and cells. Overexpression of miR-7-5p curbed cellular proliferation and promoted apoptosis. Overexpression of OSBPL11 reversed the tumorigenic properties of miR-7-5p in AML cells in vitro. Exo-miR-7-5p derived from BMSCs induced formation of AML cells prone to apoptosis and a low survival rate, with OSBPL11 expression inhibited through the PI3K/AKT/mTOR signaling pathway. Exo-miR-7-5p derived from BMSCs exhibited tumor homing effects in vitro and in vivo, and inhibited AML development.ConclusionsExo-miR-7-5p derived from BMSCs negatively regulates OSBPL11 by suppressing the phosphorylation of the PI3K/AKT/mTOR signaling pathway, thereby inhibiting AML proliferation and promoting apoptosis. The data will inform the development of AML therapies based on BMSC-derived exosomes.Graphical
Highlights
Acute myeloid leukemia (AML) is a malignant clonal hematological illness that originates from hematopoietic stem cells and accounts for approximately 70% of acute leukemia cases [1, 2]
We investigated whether bone marrow mesenchymal stem cells (BMSCs) could modulate the proliferative and apoptotic activities of AML cells via exosomes
MiR‐7‐5p is expressed at low levels in peripheral blood of AML patients and AML cell lines The levels of miR-7-5p in the peripheral blood of normal control (NC) patients and patients with AML was identified using qRTPCR
Summary
Acute myeloid leukemia (AML) is a malignant clonal hematological illness that originates from hematopoietic stem cells and accounts for approximately 70% of acute leukemia cases [1, 2]. Limitations still impede improved the remission rate and reduced recurrence after remission [4]. Molecular studies, such as second-generation sequencing and gene map analysis, have revealed that AML often involves a variety of gene variations, but the full details of its pathogenesis remain unclear [5]. Acute myeloid leukemia (AML) is a malignant clonal disease of hematopoietic stem- and progenitorcell origin. The purpose of this study was to investigate the effects of exosomes derived from bone marrow mesenchymal stem cells (BMSCs) on the regulation of AML and the underlying mechanisms mediated by microRNA (miRNA)
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