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Rôle des cellules dendritiques plasmocytoïdes dans la leucémie myélomonocytaire chronique

Abstract : Bone marrow infiltration with plasmacytoid CD123high cells was identified in a fraction of patients with a chronic myelomonocytic leukemia (CMML), but the mechanisms promoting the generation of these cells and their impact on disease evolution remain poorly known. Using a multiparametric flow cytometry assay, we detect an excess of lineage-negative mononucleated cells expressing CD45, CD123, HLA-DR, BDCA-2, BDCA-4 and CD4 in the bone marrow of 39/161 (24%) CMML patients. Conventional and electron microscopy, flow cytometry and gene expression analyses identify these cells as authentic plasmacytoid dendritic cells (pDCs). These pDCs respond to Toll-like receptor-9 (TLR9) and TLR7 agonists by producing low levels of interferon alpha and high levels of interleukin-8 (IL-8), respectively. Whole exome sequencing of sorted monocytes and pDCs detects one or several mutations that constitutively activate the Ras pathway in every pDC-rich patient, with some subclonal heterogeneity. CD34+ cells from pDC-rich CMML produce high level of pDCs in ex vivo culture, even in the absence of FMS-like tyrosine kinase 3 ligand (FLT-3L). In co-culture experiments, pDCs collected from the bone marrow of pDC-rich CMML decrease the proliferation of CD34+ cells in a dose-dependent manner. pDC increase is associated with an expansion of CD4+ regulatory T cells (Tregs). Retrospective analysis of a cohort of 216 CMML patients detected a mitigated effect of bone marrow infiltration with CD123high, TLC1+ cells on disease outcome, including a trend for a better overall survival of patients with a pDC excess but also an increased risk of leukemic transformation.
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Nolwenn Lucas. Rôle des cellules dendritiques plasmocytoïdes dans la leucémie myélomonocytaire chronique. Cancer. Université Paris Saclay (COmUE), 2017. Français. ⟨NNT : 2017SACLS372⟩. ⟨tel-02343621⟩

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