Extracellular vesicles from myelodysplastic mesenchymal stromal cells induce DNA damage and mutagenesis of hematopoietic stem cells through miRNA transfer

Meunier, Mathieu; Guttin, Audrey; Ancelet, Sarah; Laurin, David; Zannoni, Johanna; Lefebvre, Christine; Tondeur, Sylvie; Persoons, Virginie; Pezet, Mylène; Pernet‐Gallay, Karin; Chuffart, Florent; Rousseaux, Sophie; Testard, Quentin; Thévenon, Julien; Jouzier, Claire; Deleuze, Jean‐François; Laulagnier, Karine; Sadoul, Rémy; Chatellard, Christine; Hainaut, Pierre; Polack, Benoı̂t; Cahn, Jean‐Yves; Issartel, Jean-Paul; Park, Sophie

doi:10.1038/s41375-020-0738-8

Cited by 13 publications

(11 citation statements)

References 7 publications

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“…The mechanisms by which the corrupt MDS-MSCs signal to the MDS clone are diverse and only beginning to be explored. For instance, MDS-MSCs release high quantities of small extracellular vesicles (sEVs) loaded with miR-486-5p (Meunier et al, 2020). This miR-486-5p can not only promote leukemogenesis and is overexpressed in leukemic cells of Down syndrome patients (Shaham et al, 2015) but also may induce oxidative stress and apoptosis of normal HSPC and senescence in MSCs (Kim et al, 2012).…”

Section: The Bone Marrow Microenvironment In Mdsmentioning

confidence: 99%

Targeting the Microenvironment in MDS: The Final Frontier

et al. 2020

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Myelodysplastic syndromes (MDS) are a heterogeneous group of malignant disorders of hematopoietic stem and progenitor cells (HSPC), mainly characterized by ineffective hematopoiesis leading to peripheral cytopenias and progressive bone marrow failure. While clonal dominance is nearly universal at diagnosis, most genetic mutations identified in patients with MDS do not provide a conspicuous advantage to the malignant cells. In this context, malignant cells alter their adjacent bone marrow microenvironment (BME) and rely on cell extrinsic factors to maintain clonal dominance. The profoundly disturbed BME favors the myelodysplastic cells and, most importantly is detrimental to normal hematopoietic cells. Thus, the MDS microenvironment not only contributes to the observed cytopenias seen in these patients but could also negatively impact the engraftment of normal, allogeneic HSPCs in patients with MDS undergoing bone marrow transplant. Therefore, successful therapies in MDS should not only target the malignant cells but also reprogram their bone marrow microenvironment. Here, we will provide a synopsis of how drugs currently used or on the verge of being approved for the treatment of MDS may achieve this goal.

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Section: The Bone Marrow Microenvironment In Mdsmentioning

confidence: 99%

Targeting the Microenvironment in MDS: The Final Frontier

et al. 2020

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“…Specifically, leukemic exosomes initiatively deregulated normal hematopoiesis through disturbing CXCL12, SCF, KITL, IL-8, MMP9, and so on ( Huan et al, 2015 ; Corrado et al, 2016 ; Kumar et al, 2018 ). MicroRNAs from MSC exosomes even induce DNA damage and mutagenesis of HSCs for MDS initiation ( Meunier et al, 2020 ). Moreover, exosomes from MSCs even contain miR-155, a well-established microRNA that regulates hematopoietic malignancy ( Viola et al, 2016 ).…”

Section: Exosomes Link Lscs and Mscs As Major Non-cell-to-cell Contac...mentioning

confidence: 99%

Regulation of Malignant Myeloid Leukemia by Mesenchymal Stem Cells

Tan

Chen

Wong

et al. 2022

Front. Cell Dev. Biol.

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Bone marrow microenvironment (BMM) has been proven to have benefits for both normal hematopoietic stem cell niche and pathological leukemic stem cell niche. In fact, the pathological leukemia microenvironment reprograms bone marrow niche cells, especially mesenchymal stem cells for leukemia progression, chemoresistance and relapse. The growth and differentiation of MSCs are modulated by leukemia stem cells. Moreover, chromatin abnormality of mesenchymal stem cells is sufficient for leukemia initiation. Here, we summarize the detailed relationship between MSC and leukemia. MSCs can actively and passively regulate the progression of myelogenous leukemia through cell-to-cell contact, cytokine-receptor interaction, and exosome communication. These behaviors benefit LSCs proliferation and survival and inhibit physiological hematopoiesis. Finally, we describe the recent advances in therapy targeting MSC hoping to provide new perspectives and therapeutic strategies for leukemia.

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“…Of note, miR-101 suppresses cell proliferation [ 119 ] suggesting that its downregulation could be implicated in the acceleration of MDS cell proliferation and transformation to acute leukemia. Finally, Meunier et al recently found that small EVs from mesenchymal stromal cells derived from MDS patients induce ROS production promoting DNA damage and mutagenesis in healthy HSC via miRNA transfer [ 120 ]. Thus, the re-programmed MDS stromal cells secrete EVs that may induce alterations in both malignant and healthy cells that, overall, induce the progression of MDS.…”

Section: Extracellular Vesiclesmentioning

confidence: 99%

Extracellular Vesicles in Myeloid Neoplasms

Karantanou

Minciacchi

Karantanos

2022

IJMS

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Myeloid neoplasms arise from malignant primitive cells, which exhibit growth advantage within the bone marrow microenvironment (BMM). The interaction between these malignant cells and BMM cells is critical for the progression of these diseases. Extracellular vesicles (EVs) are lipid bound vesicles secreted into the extracellular space and involved in intercellular communication. Recent studies have described RNA and protein alterations in EVs isolated from myeloid neoplasm patients compared to healthy controls. The altered expression of various micro-RNAs is the best-described feature of EVs of these patients. Some of these micro-RNAs induce growth-related pathways such as AKT/mTOR and promote the acquisition of stem cell-like features by malignant cells. Another well-described characteristic of EVs in myeloid neoplasms is their ability to suppress healthy hematopoiesis either via direct effect on healthy CD34+ cells or via alteration of the differentiation of BMM cells. These results support a role of EVs in the pathogenesis of myeloid neoplasms. mainly through mediating the interaction between malignant and BMM cells, and warrant further study to better understand their biology. In this review, we describe the reported alterations of EV composition in myeloid neoplasms and the recent discoveries supporting their involvement in the development and progression of these diseases.

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Extracellular vesicles from myelodysplastic mesenchymal stromal cells induce DNA damage and mutagenesis of hematopoietic stem cells through miRNA transfer

Cited by 13 publications

References 7 publications

Targeting the Microenvironment in MDS: The Final Frontier

Targeting the Microenvironment in MDS: The Final Frontier

Regulation of Malignant Myeloid Leukemia by Mesenchymal Stem Cells

Extracellular Vesicles in Myeloid Neoplasms

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