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Myelodysplastic syndrome

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

Leukemia volume 34, pages 2249–2253 (2020)Cite this article

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Physiopathology of myelodysplastic syndrome (MDS) remains poorly understood and the role of the microenvironment is increasingly highlighted. Recent studies in mouse models demonstrate that abnormalities of mesenchymal stromal cells (MSC) contribute to the physiopathology of MDS. In particular, genetic deletion of dicer1, a gene encoding a type III RNase essential for the genesis of miRNA, in murine MSC-derived osteoprogenitors led to a pathological microenvironment generating myelodysplastic features in hematopoietic progenitors and ultimately leading to acute myeloid leukemia [1]. In human, there is an increased susceptibility to senescence of the MDS mesenchymal stem cells and defects in the support properties of the growth of hematopoietic stem cells (HSC) [2]. These observations establish a causal relationship between deregulation of the hematopoietic niche and MDS pathogenesis. However, so far only few studies have addressed the mechanisms by microenvironmental MSC and HSC exchange signals that may interfere with miRNA processing, specifically in the human MDS microenvironment.

Because DICER1 has a pivotal role in miRNA processing [3], we hypothesized that MSC from low risk MDS could present, as a consequence, a deregulated miRNA profile. Thus, the miRNA profile from four low risk MDS patients and three HD MSC were investigated using Affymetrix GeneChip miRNA 4.0 Array. We observed 16 miRNA upregulated and seven downregulated miRNA in MDS-derived MSC when compared to HD cells (Fig. 1b).

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Fig. 1: DICER1 expression in healthy donor and MDS mesenchymal stromal cells.

References

  1. Raaijmakers MH, Mukherjee S, Guo S, Zhang S, Kobayashi T, Schoonmaker JA, et al. Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature. 2010;464:852–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Geyh S, Oz S, Cadeddu RP, Frobel J, Bruckner B, Kundgen A, et al. Insufficient stromal support in MDS results from molecular and functional deficits of mesenchymal stromal cells. Leukemia. 2013;27:1841–51.

    Article  CAS  PubMed  Google Scholar 

  3. Foulkes WD, Priest JR, Duchaine TF. DICER1: mutations, microRNAs and mechanisms. Nat Rev Cancer. 2014;14:662–72.

    Article  CAS  PubMed  Google Scholar 

  4. Shaham L, Vendramini E, Ge Y, Goren Y, Birger Y, Tijssen MR, et al. MicroRNA-486-5p is an erythroid oncomiR of the myeloid leukemias of Down syndrome. Blood. 2015;125:1292–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kim YJ, Hwang SH, Lee SY, Shin KK, Cho HH, Bae YC, et al. miR-486-5p induces replicative senescence of human adipose tissue-derived mesenchymal stem cells and its expression is controlled by high glucose. Stem Cells Dev. 2012;21:1749–60.

    Article  CAS  PubMed  Google Scholar 

  6. Tkach M, Thery C. Communication by extracellular vesicles: where we are and where we need to go. Cell. 2016;164:1226–32.

    Article  CAS  PubMed  Google Scholar 

  7. Meunier M, Ancelet S, Lefebvre C, Arnaud J, Garrel C, Pezet M, et al. Reactive oxygen species levels control NF-kappaB activation by low dose deferasirox in erythroid progenitors of low risk myelodysplastic syndromes. Oncotarget. 2017;8:105510–24.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

MM has received a financial grant from Université Grenoble Alpes (Programme AGIR 2014) and from Bourse “Espoir Sandrine”. The bioinformatics and biostatistics analyses of RNA sequencing presented in this paper were performed by the Epimed platform in IAB (UGA - INSERM 1209 – CNRS UMR 5309). We thank also Cecile Martin for providing us healthy donor bone marrows. We thank Jean-Marc Moulis for the luminescence measurement facilities.

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Authors and Affiliations

  1. Department of Hematology, CHU Grenoble Alpes, Grenoble, France

    Mathieu Meunier Md, PhD, Johanna Zannoni, Claire Jouzier, Benoît Polack, Jean-Yves Cahn & Sophie Park MD, PhD

  2. CNRS UMR 5309, INSERM, U1209, Université Grenoble Alpes, Institute for Advanced Bioscience, 38700, Grenoble, France

    Mathieu Meunier Md, PhD, Sarah Ancelet, David Laurin, Johanna Zannoni, Mylène Pezet, Florent Chuffart, Sophie Rousseaux, Quentin Testard, Julien Thevenon, Claire Jouzier, Pierre Hainaut & Sophie Park MD, PhD

  3. Grenoble Institut des Neurosciences, INSERM U836, Grenoble Alpes University, Grenoble, France

    Audrey Guttin, Karine Laulagnier, Rémy Sadoul, Christine Chatellard & Jean-Paul Issartel

  4. Laboratoire de Génétique des hémopathies, CHU Grenoble Alpes, Grenoble, France

    Christine Lefebvre & Sylvie Tondeur

  5. Unité de Thérapie et d’Ingénierie Cellulaire, EFS Auvergne Rhône Alpes et UF Génétique moléculaire et maladie héréditaire et oncologie, CHUGA, Grenoble, France

    Virginie Persoons

  6. Grenoble Institut des Neurosciences, Plateforme de Microscopie électronique, Grenoble Alpes University, Grenoble, France

    Karin Pernet-Gallay

  7. Département de Génétique et Procréation, CHU Grenoble Alpes, Université Grenoble Alpes, Grenoble, France

    Quentin Testard & Julien Thevenon

  8. Bioinformatics Unit, Eurofins Biomnis, Lyon, France

    Quentin Testard

  9. Centre National de Génotypage, Institut de Génomique, Evry and Centre d’Etude du Polymorphisme Humain, 2 rue Gaston Crémieux, 91000, Paris, France

    Jean-François Deleuze

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  1. Mathieu Meunier Md, PhD
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Contributions

MM, AG, CJ, SA, DL, JZ, CJ and VP performed experiments; FC and SR performed the bioinformatics and statistical analyses of the RNAseq data; KL, CC and RM performed the nanosight analyses; KPG performed electronic microscopic pictures; JFD performed the WGS; QT, ST, CL and JT performed the bioinformatics analyses of WGS; ML performed the confocal microscopy pictures; AG and JPI analyzed the transcriptomics results; MM and SP designed the research, analyzed results and wrote the paper. PH, BP and JYC reviewed the paper.

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Correspondence to Mathieu Meunier Md, PhD or Sophie Park MD, PhD.

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Meunier, M., Guttin, A., Ancelet, S. et al. Extracellular vesicles from myelodysplastic mesenchymal stromal cells induce DNA damage and mutagenesis of hematopoietic stem cells through miRNA transfer. Leukemia 34, 2249–2253 (2020). https://doi.org/10.1038/s41375-020-0738-8

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