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Étude à l’échelle unicellulaire du compartiment des cellules souches et progénitrices des syndromes myélodysplasiques

Abstract : Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell (HSC) malignancies. The accumulation of mutations and and/or cytogenetic abnormalities in bone marrow HSC compartment confers a proliferative advantage to pathological cells. These diseases are characterized by dysplastic and ineffective hematopoiesis and evolve in 40% of cases into acute myeloid leukemia with poor prognosis. In this work, we mapped the MDS CD34+ compartment with flow cytometry, and also with single-cell RNA-Seq that allow to characterize the transcriptome at single cell level.We demonstrated that the characterization of CD34+ stem and progenitor cells of MDS by flow cytometry can differentiate them from healthy age-matched controls. Indeed, some MDS appear to have a diminished proportion of CMPMEP3 populations as compared to controls. In addition, a subgroup of MDS appears to have an increased number of B/NK progenitors relative to the other SMD and controls. We also showed that CMP and LMPP populations are over-represented in a portion of high-risk MDS. In addition, we determined that the entropy of cell distribution within the different highlighted clusters, which reflects the cell diversity of the CD34+ compartment, is significantly decreased in high-risk MDS consistent with the expansion of a pathological clone to the detriment of the diversity of normal hematopoiesis.From publicly available scRNA-Seq healthy donor bone marrow data, we have established that during hematopoietic differentiation there is a peak in intercellular gene expression variability as measured by Shannon entropy. This entropy peak is observed in all the processes studied including erythropoiesis, granulopoiesis, B lymphopoiesis as well as in the maturation process of dendritic cells. Our work showed that this entropy peak is also present in MDS hematopoiesis. In addition, we showed that MDS HSCs had significantly higher entropy than age-matched healthy controls HSCs Our data also allowed us to observe significant variations in HSC entropy associated with the response to one-year azacytidine therapy in MDS patients. There are therefore variabilities in intercellular gene expression objectified by Shannon entropy in the HSCs of MDS patients that should be compared with the dysplasia and intramedullary abortion of hematopoietic progenitors leading to cytopenias observed in these diseases.
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Charles Dussiau. Étude à l’échelle unicellulaire du compartiment des cellules souches et progénitrices des syndromes myélodysplasiques. Médecine humaine et pathologie. Université de Paris, 2020. Français. ⟨NNT : 2020UNIP7156⟩. ⟨tel-03272879⟩

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