Acute lymphoblastic leukemia-derived extracellular vesicles affect quiescence of hematopoietic stem and progenitor cells

Georgievski, Aleksandra; Michel, Anaïs; Thomas, Charles W.; Mlamla, Zandile; Barros, Jean-Paul Paı̈s de; Lemaire-Ewing, Stéphanie; Garrido, Carmen; Quéré, Ronan

doi:10.1038/s41419-022-04761-5

Cited by 11 publications

(9 citation statements)

References 82 publications

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“…The presence of TGF-β-related proteins as EVs cargoes has been established in cancer-associated fibroblast, epithelial to mesenchymal transition, as well as cancer metastasis [21]. Furthermore, EVs released from leukemia cells are responsible for the suppression of HSC functions through stromal reprogramming of niche-retention factors or as a consequence of leukemia EV-directed carrier delivery to HSC [28][29][30][31][32][33][34]. However, the presence of TGF-β-related proteins among leukemia-derived EVs cargoes has not yet been reported.…”

Section: Discussionmentioning

confidence: 99%

Bone marrow-derived extracellular vesicles carry the TGF-β signal transducer Smad2 to preserve hematopoietic stem cells in mice

et al. 2023

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SummaryExtracellular vesicles (EVs) released by cells in the bone marrow (BM) are important for regulating proliferation, differentiation, and other processes in hematopoietic stem cells (HSC). TGF-β signaling is now well known to be involved in HSC’s quiescence and maintenance, but the TGF-β pathway related to EVs is still largely unknown in the hematopoietic system. We found that the EV inhibitor Calpeptin, when injected intravenously into mice, particularly affected the in vivo production of EVs carrying phosphorylated Smad2 (p-Smad2) in mouse BM. This was accompanied with an alteration in the quiescence and maintenance of murine HSC in vivo. EVs produced by murine mesenchymal stromal MS-5 cells also showed presence of p-Smad2 as a cargo. We treated MS-5 cells with the TGF-β inhibitor SB431542 in order to produce EVs lacking p-Smad2, and discovered that its presence was required for ex vivo maintenance of HSC. In conclusion, we revealed a new mechanism involving EVs produced in the mouse BM that transport bioactive phosphorylated Smad2 as a cargo to enhance the TGF-β signaling-mediated quiescence and maintenance of HSC.

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Section: Discussionmentioning

confidence: 99%

Bone marrow-derived extracellular vesicles carry the TGF-β signal transducer Smad2 to preserve hematopoietic stem cells in mice

et al. 2023

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“…injected in NSG mice, then 18 h later, cells were recovered by centrifugation at 500× g from BM, spleen and blood, debris were removed from the supernatant by centrifugation at 10,000× g . From the supernatant, UVs were isolated by pull-down, following previously described procedures [ 68 ] with a specific kit (15254394, Thermo Fisher Scientific), and analyzed by flow cytometry.…”

Section: Methodsmentioning

confidence: 99%

Valrubicin-loaded immunoliposomes for specific vesicle-mediated cell death in the treatment of hematological cancers

Georgievski,

Bellaye,

Tournier

et al. 2024

Cell Death Dis

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We created valrubicin-loaded immunoliposomes (Val-ILs) using the antitumor prodrug valrubicin, a hydrophobic analog of daunorubicin. Being lipophilic, valrubicin readily incorporated Val-lLs that were loaded with specific antibodies. Val-ILs injected intravenously rapidly reached the bone marrow and spleen, indicating their potential to effectively target cancer cells in these areas. Following the transplantation of human pediatric B-cell acute lymphoblastic leukemia (B-ALL), T-cell acute lymphoblastic leukemia (T-ALL), or acute myeloid leukemia (AML) in immunodeficient NSG mice, we generated patient-derived xenograft (PDX) models, which were treated with Val-ILs loaded with antibodies to target CD19, CD7 or CD33. Only a small amount of valrubicin incorporated into Val-ILs was needed to induce leukemia cell death in vivo, suggesting that this approach could be used to efficiently treat acute leukemia cells. We also demonstrated that Val-ILs could reduce the risk of contamination of CD34+ hematopoietic stem cells by acute leukemia cells during autologous peripheral blood stem cell transplantation, which is a significant advantage for clinical applications. Using EL4 lymphoma cells on immunocompetent C57BL/6 mice, we also highlighted the potential of Val-ILs to target immunosuppressive cell populations in the spleen, which could be valuable in impairing cancer cell expansion, particularly in lymphoma cases. The most efficient Val-ILs were found to be those loaded with CD11b or CD223 antibodies, which, respectively, target the myeloid-derived suppressor cells (MDSC) or the lymphocyte-activation gene 3 (LAG-3 or CD223) on T4 lymphocytes. This study provides a promising preclinical demonstration of the effectiveness and ease of preparation of Val-ILs as a novel nanoparticle technology. In the context of hematological cancers, Val-ILs have the potential to be used as a precise and effective therapy based on targeted vesicle-mediated cell death.

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“…In detail, metabolomics studies revealed that ALL EVs were particularly rich in cholesterol, which accelerated the mitochondrial activation and promoted the loss of quiescence in targeted HSPC. This resulted in the exhaustion of quiescent healthy HSPC, confirmed by a reduced ex vivo ability of forming colonies [ 104 ].…”

Section: Mscs As Key Modulators Of Leukemia Onset Maintenance Progres...mentioning

confidence: 99%

Mesenchymal Stromal Cells (MSCs): An Ally of B-Cell Acute Lymphoblastic Leukemia (B-ALL) Cells in Disease Maintenance and Progression within the Bone Marrow Hematopoietic Niche

Fallati

Marzo

D’Amico

et al. 2022

Cancers

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Mesenchymal stromal cells (MSCs) are structural components of the bone marrow (BM) niche, where they functionally interact with hematopoietic stem cells and more differentiated progenitors, contributing to hematopoiesis regulation. A growing body of evidence is nowadays pointing to a further crucial contribution of MSCs to malignant hematopoiesis. In the context of B-cell acute lymphoblastic leukemia (B-ALL), MSCs can play a pivotal role in the definition of a leukemia-supportive microenvironment, impacting on disease pathogenesis at different steps including onset, maintenance and progression. B-ALL cells hijack the BM microenvironment, including MSCs residing in the BM niche, which in turn shelter leukemic cells and protect them from chemotherapeutic agents through different mechanisms. Evidence is now arising that altered MSCs can become precious allies to leukemic cells by providing nutrients, cytokines, pro-survivals signals and exchanging organelles, as hereafter reviewed. The study of the mechanisms exploited by MSCs to nurture and protect B-ALL blasts can be instrumental in finding new druggable candidates to target the leukemic BM microenvironment. Some of these microenvironment-targeting strategies are already in preclinical or clinical experimentation, and if coupled with leukemia-directed therapies, could represent a valuable option to improve the prognosis of relapsed/refractory patients, whose management represents an unmet medical need.

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Acute lymphoblastic leukemia-derived extracellular vesicles affect quiescence of hematopoietic stem and progenitor cells

Cited by 11 publications

References 82 publications

Bone marrow-derived extracellular vesicles carry the TGF-β signal transducer Smad2 to preserve hematopoietic stem cells in mice

Bone marrow-derived extracellular vesicles carry the TGF-β signal transducer Smad2 to preserve hematopoietic stem cells in mice

Valrubicin-loaded immunoliposomes for specific vesicle-mediated cell death in the treatment of hematological cancers

Mesenchymal Stromal Cells (MSCs): An Ally of B-Cell Acute Lymphoblastic Leukemia (B-ALL) Cells in Disease Maintenance and Progression within the Bone Marrow Hematopoietic Niche

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