Abstract
Exosomes are cell-generated nano-vesicles found in most biological fluids. Major components of their cargo are lipids, proteins, RNA, DNA, and non-coding RNAs. The miRNAs carried within exosomes reveal real-time information regarding disease status in leukemia and other cancers, and therefore exosomes have been studied as novel biomarkers for cancer. We investigated the impact of exosomes on cell proliferation in pediatric acute lymphocytic leukemia (PALL) and its reversal by silencing of exo-miR-181a. We isolated exosomes from the serum of PALL patients (Exo-PALL) and conditioned medium of leukemic cell lines (Exo-CM). We found that Exo-PALL promotes cell proliferation in leukemic B cell lines by gene regulation. This exosome-induced cell proliferation is a precise event with the up-regulation of proliferative (PCNA, Ki-67) and pro-survival genes (MCL-1, and BCL2) and suppression of pro-apoptotic genes (BAD, BAX). Exo-PALL and Exo-CM both show over expression of miR-181a compared to healthy donor control exosomes (Exo-HD). Specific silencing of exosomal miR-181a using a miR-181a inhibitor confirms that miR-181a inhibitor treatment reverses Exo-PALL/Exo-CM-induced leukemic cell proliferation in vitro. Altogether, this study suggests that exosomal miR-181a inhibition can be a novel target for growth suppression in pediatric lymphatic leukemia.
Highlights
Exosomes are spherical nanoparticles (30–150 nm) produced by normal and pathological cells in most body fluids such as serum, urine, breast milk, and ascites
We aimed to explore the role of pediatric acute lymphocytic leukemia (PALL) exosomes (Exo-PALL, derived from serum of children diagnosed with Acute lymphoblastic leukemia (ALL) or from conditioned medium (CM) of ALL cell lines) and its possible correlation to leukemic cell proliferation
We obtained consistent outcomes in all five Exo-PALL samples. These results suggest that Exo-miR-181a from PALL patients’ serum contribute to leukemia cell proliferation, to the results obtained from conditioned media (CM) exosomes
Summary
Exosomes are spherical nanoparticles (30–150 nm) produced by normal and pathological cells in most body fluids such as serum, urine, breast milk, and ascites. Exosomes originate from the cytoplasm of the cell by inward budding of multivesicular bodies [1]. The exosomal cargo that is transferred as such is functionally active, enabling the target cells to reprogram and redefine their immunological responses at a molecular level [4,5,6]. Exosomes derived from the tumor microenvironment can recruit and impair normal cells to contribute to the malignancy. Some reports in the literature support the fact that miRNAs carried within exosomes reveal real-time information regarding disease status in leukemia and other cancers. Our work focuses on the functional role of exosomal-miRNA-181a (exo-miR-181a) in pediatric acute lymphocytic leukemia (PALL)
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