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      Extracellular vesicles in the Chronic Myeloid Leukemia scenario: an update about the shuttling of disease markers and therapeutic molecules

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          Abstract

          Extracellular vesicles (EVs) are various sets of cell-derived membranous structures containing lipids, nucleic acids, and proteins secreted by both eukaryotic and prokaryotic cells. It is now well recognized that EVs are key intercellular communication mediators, allowing the functional transfer of bioactive chemicals from one cell to another in both healthy and pathological pathways. It is evident that the condition of the producer cells heavily influences the composition of EVs. Hence, phenotypic changes in the parent cells are mirrored in the design of the secreted EVs. As a result, EVs have been investigated for a wide range of medicinal and diagnostic uses in different hematological diseases. EVs have only recently been studied in the context of Chronic Myeloid Leukemia (CML), a blood malignancy defined by the chromosomal rearrangement t(9;22) and the fusion gene BCR-ABL1. The findings range from the impact on pathogenesis to the possible use of EVs as medicinal chemical carriers. This review aims to provide for the first time an update on our understanding of EVs as carriers of CML biomarkers for minimal residual disease monitoring, therapy response, and its management, as well as the limited reports on the use of EVs as therapeutic shuttles for innovative treatment approaches.

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          Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells.

          Exosomes are vesicles of endocytic origin released by many cells. These vesicles can mediate communication between cells, facilitating processes such as antigen presentation. Here, we show that exosomes from a mouse and a human mast cell line (MC/9 and HMC-1, respectively), as well as primary bone marrow-derived mouse mast cells, contain RNA. Microarray assessments revealed the presence of mRNA from approximately 1300 genes, many of which are not present in the cytoplasm of the donor cell. In vitro translation proved that the exosome mRNAs were functional. Quality control RNA analysis of total RNA derived from exosomes also revealed presence of small RNAs, including microRNAs. The RNA from mast cell exosomes is transferable to other mouse and human mast cells. After transfer of mouse exosomal RNA to human mast cells, new mouse proteins were found in the recipient cells, indicating that transferred exosomal mRNA can be translated after entering another cell. In summary, we show that exosomes contain both mRNA and microRNA, which can be delivered to another cell, and can be functional in this new location. We propose that this RNA is called "exosomal shuttle RNA" (esRNA).
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            Biological properties of extracellular vesicles and their physiological functions

            In the past decade, extracellular vesicles (EVs) have been recognized as potent vehicles of intercellular communication, both in prokaryotes and eukaryotes. This is due to their capacity to transfer proteins, lipids and nucleic acids, thereby influencing various physiological and pathological functions of both recipient and parent cells. While intensive investigation has targeted the role of EVs in different pathological processes, for example, in cancer and autoimmune diseases, the EV-mediated maintenance of homeostasis and the regulation of physiological functions have remained less explored. Here, we provide a comprehensive overview of the current understanding of the physiological roles of EVs, which has been written by crowd-sourcing, drawing on the unique EV expertise of academia-based scientists, clinicians and industry based in 27 European countries, the United States and Australia. This review is intended to be of relevance to both researchers already working on EV biology and to newcomers who will encounter this universal cell biological system. Therefore, here we address the molecular contents and functions of EVs in various tissues and body fluids from cell systems to organs. We also review the physiological mechanisms of EVs in bacteria, lower eukaryotes and plants to highlight the functional uniformity of this emerging communication system.
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              Exosome and Exosomal MicroRNA: Trafficking, Sorting, and Function

              Exosomes are 40–100 nm nano-sized vesicles that are released from many cell types into the extracellular space. Such vesicles are widely distributed in various body fluids. Recently, mRNAs and microRNAs (miRNAs) have been identified in exosomes, which can be taken up by neighboring or distant cells and subsequently modulate recipient cells. This suggests an active sorting mechanism of exosomal miRNAs, since the miRNA profiles of exosomes may differ from those of the parent cells. Exosomal miRNAs play an important role in disease progression, and can stimulate angiogenesis and facilitate metastasis in cancers. In this review, we will introduce the origin and the trafficking of exosomes between cells, display current research on the sorting mechanism of exosomal miRNAs, and briefly describe how exosomes and their miRNAs function in recipient cells. Finally, we will discuss the potential applications of these miRNA-containing vesicles in clinical settings.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                08 January 2024
                2023
                : 13
                : 1239042
                Affiliations
                [1] 1 Department of Clinical and Experimental Sciences, University of Brescia, Unit of Bone Marrow Transplantation, Azienda Socio Sanitaria Territoriale (ASST) Spedali Civili of Brescia , Brescia, Italy
                [2] 2 Lab CREA (Centro di Ricerca Emato-oncologica Associazione italiana contro le leucemie, linfomi e mieloma-AIL), ASST Spedali Civili of Brescia , Brescia, Italy
                [3] 3 Department of Medical Sciences and Public Health, University of Cagliari, Hematology Unit, Businco Hospital , Cagliari, Italy
                Author notes

                Edited by: Mario Tiribelli, University of Udine, Italy

                Reviewed by: Cosimo Cumbo, University of Bari Aldo Moro, Italy

                Jafar Rezaie, Urmia University of Medical Sciences, Iran

                *Correspondence: Olga Mulas, mulasolga@ 123456unica.it

                †These authors have contributed equally to this work

                Article
                10.3389/fonc.2023.1239042
                10800789
                38260856
                bff8fc0b-1bf0-435e-b106-3e633b3a65da
                Copyright © 2024 Bernardi, Mulas, Mutti, Costa, Russo and La Nasa

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 12 June 2023
                : 27 November 2023
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 87, Pages: 10, Words: 5419
                Funding
                The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The APC was funded by Department of Medical Sciences and Public Health, University of Cagliari and Dipartimento di Scienze Cliniche e Sperimentali, Università degli studi di Brescia, viale Europa 11, 25123, Brescia.
                Categories
                Oncology
                Review
                Custom metadata
                Hematologic Malignancies

                Oncology & Radiotherapy
                chronic myeloid leukemia,extracellular vesicles,exosomes,vesicular markers,therapeutic shuttle,tkis

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